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TW201628630A - Cell death-inducing agent, cell growth-inhibiting agent, and pharmaceutical composition for treatment of disease caused by abnormal cell growth - Google Patents

Cell death-inducing agent, cell growth-inhibiting agent, and pharmaceutical composition for treatment of disease caused by abnormal cell growth Download PDF

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TW201628630A
TW201628630A TW104143910A TW104143910A TW201628630A TW 201628630 A TW201628630 A TW 201628630A TW 104143910 A TW104143910 A TW 104143910A TW 104143910 A TW104143910 A TW 104143910A TW 201628630 A TW201628630 A TW 201628630A
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田中洋行
味吞憲二郎
新津洋司郎
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日東電工股份有限公司
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Abstract

It is intended to induce cell death and inhibit cell growth for cancer cells. The agents of the present invention comprise, as active ingredients, a drug inhibiting GST-[pi] and a drug inhibiting a homeostasis-related protein that exhibits synthetic lethality when inhibited together with GST-[pi].

Description

細胞死亡誘導劑、細胞增殖抑制劑及起因於細胞增殖異常之疾病治療用醫藥組合物 Cell death inducing agent, cell proliferation inhibitor, and pharmaceutical composition for treating diseases caused by abnormal cell proliferation

本發明係關於一種針對癌細胞之細胞死亡誘導劑、細胞增殖抑制劑、起因於細胞增殖異常之疾病治療用醫藥組合物，進而關於一種篩選細胞死亡誘導劑及/或細胞增殖抑制劑之方法。 The present invention relates to a cell death inducing agent for cancer cells, a cell proliferation inhibitor, a pharmaceutical composition for treating a disease caused by abnormal cell proliferation, and a method for screening a cell death inducing agent and/or a cell proliferation inhibitor.

作為起因於細胞增殖異常之疾病，可列舉癌作為典型之例。癌係由於基因之突變或非遺傳性之異常等而導致細胞不受控制地增殖之疾病。作為癌之基因異常，已有大量報告(例如非專利文獻1等)，多數報告認為與細胞之增殖、分化、存活相關之訊號傳遞存在某些關聯。又，由於該基因異常，由正常分子構成之細胞內之訊號傳遞發生異常，此導致特定之訊號級聯之活化或減活，最終成為引起細胞之異常增殖之一個原因。 As a disease caused by abnormal cell proliferation, cancer is exemplified as a typical example. A cancer system is a disease in which cells are uncontrolled to proliferate due to mutations in genes or abnormalities such as non-hereditary diseases. A large number of reports have been reported as cancer gene abnormalities (for example, Non-Patent Document 1), and most reports suggest that there is some correlation with signal transmission related to cell proliferation, differentiation, and survival. Moreover, due to the abnormality of the gene, the signal transmission in the cells composed of normal molecules is abnormal, which leads to the activation or deactivation of the specific signal cascade, and finally becomes a cause of abnormal proliferation of cells.

初期之癌症治療主要著眼於抑制細胞增殖本身，但該治療亦會於生理上抑制正常細胞之增殖，因此會伴有脫毛、消化系統障礙、骨髓抑制等副作用。因此，為了抑制該副作用，業界正推進以癌所特有之基因異常、或訊號傳遞之異常為標靶之分子標靶藥等基於新思路之 癌症治療藥。 The initial cancer treatment mainly focuses on inhibiting cell proliferation itself, but the treatment also physiologically inhibits the proliferation of normal cells, and thus is accompanied by side effects such as hair removal, digestive system disorders, and myelosuppression. Therefore, in order to suppress this side effect, the industry is advancing new molecular ideas based on molecular targets such as cancer-specific genetic abnormalities or signal transmission abnormalities. Cancer treatment drugs.

認為癌係由於各種癌基因、癌抑制基因、DNA修復酶基因等之異常累積於同一細胞而引發。作為癌基因，已知有RAS基因、FOS基因、MYC基因及BCL-2基因等。於癌所特有之基因異常中，於胰腺癌之約95%、大腸癌之約45%、其他多種癌中，對於KRAS基因以高頻度可見變異。KRAS蛋白質係局部存在於細胞膜之內側之G蛋白質。形成KRAS等之RAS將C-RAF或B-RAF等RAF活化，RAF繼續將MEK活化，MEK將MAPK活化之級聯。若於KRAS引起點突變，則GTPase活性會降低，維持結合有GTP之活性型，藉此恆常性地持續向下游之訊號，結果細胞增殖發生異常。以KRAS基因為代表，因癌基因而於細胞增殖方面發生異常，由此細胞之癌化進行，並且進展為作為疾病之癌。 It is thought that the cancer system is caused by the accumulation of abnormalities such as various oncogenes, cancer suppressor genes, and DNA repair enzyme genes in the same cell. As the oncogene, a RAS gene, a FOS gene, a MYC gene, and a BCL-2 gene are known. Among the genetic abnormalities specific to cancer, about 95% of pancreatic cancer, about 45% of colorectal cancer, and various other cancers, KRAS genes are mutated at high frequency. The KRAS protein is a G protein that is locally present on the inside of the cell membrane. RAS forming KRAS or the like activates RAF such as C-RAF or B-RAF, RAF continues to activate MEK, and MEK cascades MAPK activation. If a point mutation occurs in KRAS, the GTPase activity is lowered, and the active form that binds to GTP is maintained, thereby continuously continuing the downstream signal, resulting in abnormal cell proliferation. As a representative of the KRAS gene, an abnormality occurs in cell proliferation due to an oncogene, whereby cell cancer progresses and progresses to cancer as a disease.

且說，作為對包含麩胱甘肽進行催化之酶之一的麩胱甘肽-S-轉移酶(GST)已知為使藥劑等物質與麩胱甘肽(GSH)偶聯而形成水溶性物質之酶。GST係基於胺基酸序列，代表性者分為α、μ、ω、π、θ及ζ之6種同功異構酶。其中，尤其是GST-π(glutathione S-transferase pi，亦稱為GSTP1)之表現於各種癌細胞中增大，此情況被指摘可能為針對一部分抗癌劑之耐性之一個原因。實際上，已知對於過度表現GST-π且顯示出藥物耐性之癌細胞系，若使針對GST-π之反義DNA或GST-π抑制劑對其發揮作用，則會抑制藥劑耐性(非專利文獻2~4)。進而，於最近之報告中，報告有若使針對GST-π之siRNA作用於過度表現GST-π之雄激素非依賴性攝護腺癌細胞系，則會抑制其增殖，而增大細胞凋亡(非專利文獻5)。 Further, glutathione-S-transferase (GST), which is one of the enzymes catalyzing glutathione, is known to couple a substance such as a drug with glutathione (GSH) to form a water-soluble substance. The enzyme. GST is based on an amino acid sequence, and is representatively divided into six isomeric isomerases of α, μ, ω, π, θ, and ζ. Among them, in particular, GST-π (glutathione S-transferase pi, also known as GSTP1) is expressed in various cancer cells, and this situation may be cited as a cause of resistance to a part of anticancer agents. In fact, it is known that for cancer cell lines that overexpress GST-π and exhibit drug tolerance, if antisense DNA or GST-π inhibitor against GST-π acts on it, drug resistance is inhibited (non-patent Literature 2~4). Furthermore, in a recent report, it was reported that if GST-π-targeted siRNA is applied to an androgen-independent prostate cancer cell line that overexpresses GST-π, it will inhibit proliferation and increase apoptosis ( Non-patent document 5).

又，關於GST-π，已知其會與c-Jun N末端激酶(JNK)形成複合體，而抑制JNK活性(非專利文獻6)。進而，關於GST-π，已知其與和細胞之應力應答相關之蛋白質之S-麩胱甘肽化相關(非專利文獻7)。進 而又，關於GST-π，已知其有助於針對由活性氧種(ROS)誘導之細胞死亡的保護作用(非專利文獻8)。如此，可理解GST中之GST-π具有各種特徵、功能。 Further, GST-π is known to form a complex with c-Jun N-terminal kinase (JNK) and inhibit JNK activity (Non-Patent Document 6). Further, GST-π is known to be associated with S-glutathionylation of a protein related to stress response of cells (Non-Patent Document 7). Enter Further, regarding GST-π, it is known to contribute to the protection against cell death induced by reactive oxygen species (ROS) (Non-Patent Document 8). Thus, it can be understood that GST-π in GST has various features and functions.

報告有若使針對GST-π之siRNA作用於KRAS具有變異之癌細胞系，則會抑制Akt之活化，自嗜作用增大，但細胞凋亡之誘導成為中等程度(非專利文獻9)。專利文獻1中揭示有藉由將抑制GST-π之藥物、與3-甲基腺嘌呤等自嗜作用抑制劑作為活性成分，可誘導癌細胞之細胞凋亡。進而，專利文獻2中揭示有若同時抑制GST-π與Akt等之表現，則會抑制細胞增殖，誘導細胞死亡，並且因GST-π之表現抑制而被誘導之自嗜作用因同時抑制Akt等之表現而得到顯著抑制。 When the siRNA against GST-π is applied to a cancer cell line having a mutation in KRAS, activation of Akt is inhibited, and self-tropic action is increased, but induction of apoptosis is moderate (Non-Patent Document 9). Patent Document 1 discloses that apoptosis of cancer cells can be induced by using a drug that inhibits GST-π and a self-tropic inhibitor such as 3-methyladenine as an active ingredient. Further, Patent Document 2 discloses that when GST-π and Akt are simultaneously suppressed, cell proliferation is inhibited, cell death is induced, and self-adhesive action induced by inhibition of GST-π inhibition simultaneously suppresses Akt or the like. Significant inhibition of performance.

然而，於癌細胞中，關於GST-π之表現與細胞增殖或細胞死亡之關係、或關於訊號傳遞之GST-π之功能等並未充分得到闡明。 However, in cancer cells, the relationship between the expression of GST-π and cell proliferation or cell death, or the function of GST-π for signal transmission has not been fully elucidated.

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

[專利文獻1]WO2012/176282 [Patent Document 1] WO2012/176282

[專利文獻2]WO2014/098210 [Patent Document 2] WO2014/098210

[非專利文獻] [Non-patent literature]

[非專利文獻1]Futreal et al., Nat Rev Cancer. 2004;4(3):177-83 [Non-Patent Document 1] Futreal et al., Nat Rev Cancer. 2004; 4(3): 177-83

[非專利文獻2]Takahashi and Niitsu, Gan To Kagaku Ryoho. 1994;21(7):945-51 [Non-Patent Document 2] Takahashi and Niitsu, Gan To Kagaku Ryoho. 1994; 21(7): 945-51

[非專利文獻3]Ban et al., Cancer Res. 1996;56(15):3577-82 [Non-Patent Document 3] Ban et al., Cancer Res. 1996; 56(15): 3577-82

[非專利文獻4]Nakajima et al., J Pharmacol Exp Ther. 2003;306(3):861-9 [Non-Patent Document 4] Nakajima et al., J Pharmacol Exp Ther. 2003; 306(3): 861-9

[非專利文獻5]Hokaiwado et al., Carcinogenesis. 2008;29(6):1134-8 [Non-Patent Document 5] Hokaiwado et al., Carcinogenesis. 2008;29(6):1134-8

[非專利文獻6]Adler et.al, EMBO J. 1999, 18, 1321-1334 [Non-Patent Document 6] Adler et.al, EMBO J. 1999, 18, 1321-1334

[非專利文獻7]Townsend, et.al, J. Biol. Chem. 2009, 284, 436-445 [Non-Patent Document 7] Townsend, et. al, J. Biol. Chem. 2009, 284, 436-445

[非專利文獻8]Yin et.al, Cancer Res. 2000 60, 4053-4057 [Non-Patent Document 8] Yin et. al, Cancer Res. 2000 60, 4053-4057

[非專利文獻9]Nishita et al., AACR 102nd Annual Meeting, Abstract No. 1065 [Non-Patent Document 9] Nishita et al., AACR 102nd Annual Meeting, Abstract No. 1065

因此，本發明之目的在於提供一種對於癌細胞具有細胞死亡誘導作用及/或細胞增殖抑制作用之劑，提供一種起因於細胞增殖異常之疾病治療用醫藥組合物，提供一種篩選細胞死亡誘導劑及/或細胞增殖抑制劑之方法。 Accordingly, an object of the present invention is to provide a pharmaceutical composition for treating a disease caused by a cell death-inducing effect and/or a cell proliferation-inhibiting effect, which provides a cell death inducing agent and a cell death-inducing agent. / or method of cell proliferation inhibitor.

鑒於上述目的，本發明者等人進行了努力研究，結果發現：於癌細胞中，若抑制GST-π並且抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質，則與抑制任一者之情形相比，更強力地抑制細胞死亡，更強力抑制細胞增殖，從而完成本發明。本發明包括以下內容。 In view of the above, the inventors of the present invention conducted diligent research and found that, in cancer cells, if GST-π is inhibited and inhibition is suppressed together with GST-π, the constantity of synthetic lethality is maintained. The protein completes the present invention by inhibiting cell death more strongly and inhibiting cell proliferation more strongly than in the case of inhibiting either. The present invention includes the following.

(1)一種癌細胞之細胞死亡誘導劑，其包含抑制GST-π之藥物、與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之藥物作為有效成分。 (1) A cell death inducing agent for cancer cells, comprising a drug that inhibits GST-π and a drug that inhibits the maintenance of a fatality-maintaining related protein if it is inhibited together with GST-π as an active ingredient .

(2)一種癌細胞之細胞增殖抑制劑，其包含抑制GST-π之藥物、與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之藥物作為有效成分。 (2) A cell proliferation inhibitor of a cancer cell comprising, as an active ingredient, a drug which inhibits GST-π and a drug which inhibits the expression of a synthetic lethality-maintaining protein if it is inhibited together with GST-π .

(3)如(1)或(2)之劑，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 (3) The agent according to (1) or (2), characterized in that the above-mentioned constant maintenance-maintaining related protein which exhibits synthetic lethality together with inhibition of GST-π is selected from a cell cycle-regulating protein and an anti-cell Proteins in a group consisting of proteins associated with death-related proteins and PI3K signaling pathways.

(4)如(3)之劑，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種細胞週期調節蛋白質。 (4) The agent according to (3), wherein the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, At least one cell cycle regulatory protein of the group consisting of RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, and MYLK.

(5)如(3)之劑，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 (5) The agent according to (3), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3 and MCMDC1. At least one protein in the population.

(6)如(3)之劑，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 (6) The agent according to (3), wherein the anti-apoptosis-related protein which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, At least one anti-apoptosis-related protein of the group consisting of AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A.

(7)如(3)之劑，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 (7) The agent according to (3), characterized in that the PI3K signal transmission path-related protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, At least one PI3K signal transmission pathway-related protein in a group consisting of RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

(8)如(1)或(2)之劑，其特徵在於：上述藥物係選自由RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等中之至少1種之載體所組成之群中之物質。 (8) The agent according to (1) or (2), wherein the drug is selected from the group consisting of an RNAi molecule, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and at least one of the expressions a substance in a group consisting of carriers.

(9)如(1)或(2)之劑，其特徵在於：上述抑制恆常性維持相關蛋白質之藥物係作用於該恆常性維持相關蛋白質之化合物。 (9) The agent according to (1) or (2), wherein the drug which inhibits the constantity-maintaining related protein acts on the compound which maintains the related protein in the constantity.

(10)如(1)之劑，其特徵在於：誘導細胞凋亡。 (10) The agent according to (1), which is characterized in that apoptosis is induced.

(11)如(1)或(2)之劑，其特徵在於：上述癌細胞係高度表現GST-π 之癌細胞。 (11) The agent according to (1) or (2), wherein the cancer cell line highly expresses GST-π Cancer cells.

(12)一種起因於細胞之增殖異常之疾病治療用醫藥組合物，其包含如上述(1)至(11)中任一項之劑。 (12) A pharmaceutical composition for treating a disease caused by abnormal proliferation of cells, which comprises the agent according to any one of the above (1) to (11).

(13)如(12)之醫藥組合物，其特徵在於：上述疾病為癌。 (13) The pharmaceutical composition according to (12), wherein the disease is cancer.

(14)如(13)之醫藥組合物，其特徵在於：上述癌係高度表現GST-π之癌。 (14) The pharmaceutical composition according to (13), wherein the cancer system is highly cancerous of GST-π.

(15)一種與抑制GST-π之藥物一併使用之癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之篩選方法，其包括選出抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物。 (15) A method for screening a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell used together with a drug for inhibiting GST-π, which comprises selecting a inhibition to exhibit synthesis if it is inhibited together with GST-π A fatal constant that maintains the drug associated with the protein.

(16)如(15)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 (16) The screening method according to (15), characterized in that the above-mentioned constant maintenance-maintaining related protein exhibiting synthetic lethality together with inhibition of GST-π is selected from a cell cycle regulating protein and an anti-apoptosis-related protein. And the protein in the group consisting of proteins related to the PI3K signal transmission pathway.

(17)如(16)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種蛋白質。 (17) The screening method according to (16), wherein the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, and MCM10. At least one of a group consisting of RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, and MYLK.

(18)如(16)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 (18) The screening method according to (16), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3 and MCMDC1. At least one protein in the group.

(19)如(16)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、 MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 (19) The screening method according to (16), characterized in that the anti-apoptosis-related protein line which exhibits synthetic lethality together with the inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5. , AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1 At least one anti-apoptosis-related protein of the group consisting of MPO, MTL5, MYBL2, and MYO18A.

(20)如(16)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 (20) The screening method according to (16), characterized in that the PI3K signal transmission path-related protein line which exhibits a synthetic lethality together with the inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, and PIK3CG. At least one of the PI3K signaling pathway-related proteins of the group consisting of RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

(21)如(15)至(20)中任一項之篩選方法，其包括：使受檢物質接觸癌細胞之步驟；測定上述細胞中之上述恆常性維持相關蛋白質之表現量之步驟；及選出與於受檢物質之非存在下進行測定之情形時相比該表現量降低之情形時抑制上述恆常性維持相關蛋白質之藥物的步驟。 (21) The screening method according to any one of (15) to (20), comprising: a step of contacting the test substance with the cancer cell; and measuring the above-described constant in the cell to maintain the expression amount of the related protein; And a step of suppressing the above-described drug for maintaining the constantity-maintaining protein when the amount of expression is lowered as compared with the case where the measurement is performed in the absence of the test substance.

(22)一種癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之篩選方法，其與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之藥物一併使用，且包括選出抑制GST-π之藥物。 (22) A method for screening a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell, which is a drug which inhibits the expression of a synthetic lethality-maintaining related protein if it is inhibited together with GST-π And used, and includes the selection of drugs that inhibit GST-π.

(23)如(22)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 (23) The screening method according to (22), characterized in that the above-mentioned constant maintenance-maintaining related protein exhibiting synthetic lethality together with inhibition of GST-π is selected from a cell cycle regulating protein and an anti-apoptosis-related protein. And the protein in the group consisting of proteins related to the PI3K signal transmission pathway.

(24)如(23)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種蛋白質。 (24) The screening method according to (23), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, and MCM10. At least one of a group consisting of RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, and MYLK.

(25)如(23)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、 CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 (25) The screening method according to (23), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from p21, RNPC1. At least one of the group consisting of CCNL1, MCM8, CCNB3, and MCMDC1.

(26)如(23)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 (26) The screening method according to (23), characterized in that the anti-apoptosis-related protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5 At least one anti-apoptosis-related protein of the group consisting of AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A.

(27)如(23)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 (27) The screening method according to (23), characterized in that the PI3K signal transmission pathway-related protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG At least one of the PI3K signaling pathway-related proteins of the group consisting of RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

(28)如(22)至(27)中任一項之篩選方法，其包括：使受檢物質接觸癌細胞之步驟；測定上述細胞中之GST-π之表現量之步驟；及選出與於受檢物質之非存在下進行測定之情形相比該表現量降低之情形時抑制上述GST-π之藥物的步驟。 (28) The screening method according to any one of (22) to (27), comprising: a step of contacting the test substance with the cancer cell; a step of measuring the amount of GST-π expression in the cell; and selecting and The step of suppressing the above-mentioned GST-π drug in the case where the measurement is performed in the absence of the test substance as compared with the case where the amount of the measurement is decreased.

(29)一種細胞死亡誘導劑及/或細胞增殖抑制劑之篩選方法，其包括選出抑制GST-π及若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物。 (29) A method for screening a cell death inducing agent and/or a cell proliferation inhibitor, which comprises selecting a GST-π-inhibiting protein and, if inhibited together with GST-π, exhibiting a synthetic lethality to maintain a related protein drug.

(30)如(29)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 (30) The screening method according to (29), characterized in that the above-mentioned constant maintenance-maintaining related protein exhibiting synthetic lethality together with inhibition of GST-π is selected from a cell cycle regulating protein and an anti-apoptosis-related protein. And the protein in the group consisting of proteins related to the PI3K signal transmission pathway.

(31)如(30)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、 p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種蛋白質。 (31) The screening method according to (30), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, At least one of the group consisting of p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, and MYLK.

(32)如(30)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 (32) The screening method according to (30), characterized in that the cell cycle-regulating protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3 and MCMDC1. At least one protein in the group.

(33)如(30)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 (33) The screening method according to (30), characterized in that the anti-apoptosis-related protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5 At least one anti-apoptosis-related protein of the group consisting of AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A.

(34)如(30)之篩選方法，其特徵在於：與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 (34) The screening method according to (30), characterized in that the PI3K signal transmission path-related protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, and PIK3CG. At least one of the PI3K signaling pathway-related proteins of the group consisting of RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

(35)如(29)至(34)中任一項之篩選方法，其包括：使受檢物質接觸癌細胞之步驟；測定上述細胞中之GST-π之表現量及若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之表現量的步驟；及選出與於受檢物質之非存在下進行測定之情形相比GST-π之表現量及若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之表現量均降低之情形時，抑制GST-π及若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之藥物的步驟。 (35) The screening method according to any one of (29) to (34), comprising: the step of contacting the test substance with the cancer cell; determining the amount of GST-π expression in the cell and the GST-π And being inhibited, the step of demonstrating the consistency of the synthetic lethality to maintain the expression amount of the related protein; and selecting the amount of GST-π expression compared with the case where the measurement is performed in the non-existence of the test substance, and if and GST- When π is suppressed together, it is shown that the constantity of synthetic lethality keeps the expression of the related protein decreased. When GST-π is suppressed and if it is suppressed together with GST-π, it shows the constant of synthetic lethality. The step of maintaining the drug of the relevant protein.

本說明書包括成為本申請之優先權基礎之日本專利申請號2014- 266198號、2015-135494號、2015-247725號之揭示內容。 The present specification includes Japanese Patent Application No. 2014- which is the priority of the present application. The disclosures of 266198, 2015-135494, and 2015-247725.

根據本發明之細胞死亡誘導劑，可對癌細胞非常強力地誘導細胞死亡。因此，本發明之細胞死亡誘導劑可作為起因於癌細胞之增殖異常之疾病治療用醫藥組合物而發揮出非常高之藥效。 According to the cell death inducing agent of the present invention, cell death can be induced very strongly against cancer cells. Therefore, the cell death inducing agent of the present invention can exert a very high pharmacological effect as a pharmaceutical composition for treating a disease caused by abnormal proliferation of cancer cells.

又，根據本發明之細胞增殖抑制劑，可對癌細胞非常強力地抑制細胞增殖。因此，本發明之細胞增殖抑制劑可作為起因於癌細胞之增殖異常之疾病治療用醫藥組合物而發揮出非常高之藥效。 Further, according to the cell proliferation inhibitor of the present invention, cell proliferation can be inhibited very strongly against cancer cells. Therefore, the cell proliferation inhibitor of the present invention can exert a very high pharmacological effect as a pharmaceutical composition for treating diseases caused by abnormal proliferation of cancer cells.

進而，根據本發明之篩選方法，可選出對癌細胞非常強力地誘導細胞死亡及/或抑制細胞增殖之藥劑。 Further, according to the screening method of the present invention, an agent which induces cell death and/or inhibits cell proliferation very strongly against cancer cells can be selected.

圖1係表示測定使抑制GST-π之表現之siRNA及/或抑制p21之表現之siRNA作用時之表現變異型KRAS之細胞中之GST-π之mRNA及p21之mRNA之結果的特性圖。 Fig. 1 is a characteristic diagram showing the results of measuring the mRNA of GST-π and the mRNA of p21 in cells expressing variant KRAS when siRNA which inhibits the expression of GST-π and/or siRNA which inhibits the expression of p21.

圖2係表示經時地定量將GST-π一併敲減時p21之mRNA之結果的特性圖。 Fig. 2 is a characteristic diagram showing the results of quantifying the mRNA of p21 when GST-π is knocked down together over time.

圖3係表示測定將GST-π及p21一併敲減時之細胞數之結果的特性圖。 Fig. 3 is a characteristic diagram showing the results of measuring the number of cells when GST-π and p21 were knocked down together.

圖4係表示測定將GST-π及p21一併敲減3次時之細胞數之結果的特性圖。 Fig. 4 is a characteristic diagram showing the results of measuring the number of cells when GST-π and p21 were knocked down three times together.

圖5係表示測定將GST-π及p21一併敲減3次時之細胞數之結果的特性圖。 Fig. 5 is a characteristic diagram showing the results of measuring the number of cells when GST-π and p21 were knocked down three times together.

圖6係表示拍攝將GST-π及p21一併敲減3次時之A549細胞之相位差圖像的照片。 Fig. 6 is a photograph showing a phase difference image of A549 cells when GST-π and p21 were knocked down three times together.

圖7係拍攝將GST-π及p21一併敲減3次時之MIAPaCa-2細胞之相位差圖像的照片。 Fig. 7 is a photograph showing a phase difference image of MIAPaCa-2 cells when GST-π and p21 were knocked down three times together.

圖8係拍攝將GST-π及p21一併敲減3次時之PANC-1細胞之相位差圖像的照片。 Fig. 8 is a photograph showing a phase difference image of PANC-1 cells when GST-π and p21 were knocked down three times together.

圖9係拍攝將GST-π及p21一併敲減3次時之HCT116細胞之相位差圖像的照片。 Fig. 9 is a photograph showing a phase difference image of HCT116 cells when GST-π and p21 were knocked down three times together.

圖10係拍攝將GST-π敲減3次並進行β-半乳糖苷酶染色時之M7609細胞之相位差圖像的照片。 Fig. 10 is a photograph showing a phase difference image of M7609 cells when GST-π was knocked down three times and subjected to ?-galactosidase staining.

圖11係表示定量將GST-π及p21一併敲減時之PUMA基因之表現之結果的特性圖。 Fig. 11 is a characteristic diagram showing the results of quantifying the expression of the PUMA gene when GST-π and p21 are collectively knocked down.

圖12係表示對分別單獨敲減GST-π及顯示出合成致死性之候補蛋白質(細胞週期調節蛋白質)時、及一併敲減時之相對存活率進行比較之結果的特性圖。 Fig. 12 is a characteristic diagram showing the results of comparing the relative survival rates when GST-π is separately knocked down and the candidate protein (cell cycle regulatory protein) exhibiting synthetic lethality is knocked down.

圖13係表示對分別單獨敲減GST-π及顯示出合成致死性之候補蛋白質(抗細胞凋亡相關蛋白質)時、及一併敲減時之相對存活率進行比較之結果的特性圖。 Fig. 13 is a characteristic diagram showing the results of comparing the relative survival rates when GST-π is separately knocked down and the candidate protein exhibiting synthetic lethality (anti-apoptosis-related protein) is knocked down.

圖14係表示對分別單獨敲減GST-π及顯示出合成致死性之候補蛋白質(PI3K訊號傳遞路徑相關蛋白質)時、及一併敲減時之相對存活率進行比較之結果的特性圖。 Fig. 14 is a characteristic diagram showing the results of comparing the relative survival rates when GST-π alone and the synthetic lethal candidate protein (PI3K signal transmission pathway-related protein) are knocked down and when knocked down together.

圖15係表示對分別單獨敲減GST-π及MYLK時、及一併敲減時之相對存活率進行比較之結果的特性圖。 Fig. 15 is a characteristic diagram showing the results of comparing the relative survival rates when GST-π and MYLK are separately knocked down and knocked down together.

本發明之細胞死亡誘導劑及細胞增殖抑制劑包含抑制GST-π之藥物、與抑制若與GST-π一併被抑制則表示合成致死性之恆常性維持相關蛋白質的藥物作為有效成分。本發明之細胞死亡誘導劑及細胞增殖抑制劑係對癌細胞顯示出細胞死亡誘導效果及細胞增殖抑制效果者。此處，癌細胞係起因於基因(癌相關基因)而顯示出增殖異常之細胞。 The cell death inducing agent and the cell proliferation inhibitor of the present invention comprise, as an active ingredient, a drug which inhibits GST-π and a protein which inhibits the synthesis of a lethality-maintaining-related protein when it is inhibited together with GST-π. The cell death inducing agent and the cell proliferation inhibitor of the present invention exhibit a cell death-inducing effect and a cell proliferation inhibitory effect on cancer cells. Here, the cancer cell is a cell that exhibits abnormal proliferation due to a gene (cancer-associated gene).

例如，作為癌相關基因中之癌基因，可列舉：KRAS基因、FOS 基因、MYC基因、BCL-2基因及SIS基因等。又，作為癌相關基因中之癌抑制基因，可列舉：RB基因、p53基因、BRCA1基因、NF1基因及p73基因等。其中，作為癌細胞，並不限定於與該等具體之癌相關基因相關之癌細胞，亦可廣泛地應用於顯示出細胞增殖異常之細胞。 For example, as an oncogene in a cancer-related gene, KRAS gene, FOS can be cited. Gene, MYC gene, BCL-2 gene and SIS gene. Further, examples of the cancer suppressor gene in the cancer-related gene include an RB gene, a p53 gene, a BRCA1 gene, an NF1 gene, and a p73 gene. Among them, cancer cells are not limited to cancer cells associated with these specific cancer-related genes, and can be widely applied to cells exhibiting abnormal cell proliferation.

尤其是，本發明之細胞死亡誘導劑及細胞增殖抑制劑較佳為應用於癌細胞中之高度表現GST-π之癌細胞。此處，高度表現GST-π之癌細胞意指顯示出細胞增殖異常之細胞(所謂癌細胞)中GST-π之表現量與正常細胞相比顯著高之細胞。再者，GST-π之表現量可依據RT-PCR或微陣列等規定方法進行測定。 In particular, the cell death inducing agent and cell proliferation inhibitor of the present invention are preferably applied to cancer cells which highly express GST-π in cancer cells. Here, the cancer cell which highly expresses GST-π means a cell in which the amount of GST-π expression in cells which are abnormal in cell proliferation (so-called cancer cells) is significantly higher than that of normal cells. Furthermore, the amount of expression of GST-π can be measured according to a prescribed method such as RT-PCR or microarray.

較多情形時，作為高度表現GST-π之癌細胞之一例，可列舉表現變異型KRAS之癌細胞。即，本發明中之細胞死亡誘導劑及細胞增殖抑制劑較佳為應用於表現變異型KRAS之癌細胞。 In many cases, as an example of a cancer cell which highly expresses GST-π, a cancer cell exhibiting a variant KRAS can be cited. That is, the cell death inducing agent and the cell proliferation inhibitor of the present invention are preferably used for cancer cells exhibiting variant KRAS.

所謂變異型KRAS意指具有於野生型KRAS之胺基酸序列中導入有缺失、置換、加成、插入之變異之胺基酸序列的蛋白質。再者，此處變異型KRAS中之變異係所謂功能獲得性變異(gain of function)。即，表現變異型KRAS之細胞起因於該等變異，例如藉由GTPase活性降低，維持結合有GTP之活性型，而恆常性地持續向下游之訊號，結果與表現野生型KRAS之細胞相比，於細胞增殖方面產生異常。作為編碼變異型KRAS之基因，可列舉：野生型KRAS基因中之密碼子12、密碼子13及密碼子61中至少1處具有變異之基因。尤其作為變異型KRAS，較佳為密碼子12及13之變異。具體而言，可列舉KRAS基因之密碼子12所編碼之甘胺酸置換為絲胺酸、天冬胺酸、纈胺酸、半胱胺酸、丙胺酸或精胺酸之變異、KRAS基因之密碼子13所編碼之甘胺酸變為天冬胺酸之變異。 The variant KRAS means a protein having an amino acid sequence introduced with a deletion, substitution, addition or insertion mutation in the amino acid sequence of wild-type KRAS. Furthermore, the variation in the variant KRAS here is the so-called gain of function. That is, cells exhibiting variant KRAS are caused by such mutations, for example, by a decrease in GTPase activity, maintaining an active form that binds to GTP, and constantly continuing downstream signals, resulting in comparison with cells exhibiting wild-type KRAS. , producing abnormalities in cell proliferation. Examples of the gene encoding the variant KRAS include a gene having a mutation in at least one of codon 12, codon 13 and codon 61 in the wild type KRAS gene. Particularly as variant KRAS, variations of codons 12 and 13 are preferred. Specifically, a glycine acid encoded by codon 12 of the KRAS gene is substituted with a mutation of serine, aspartic acid, proline, cysteine, alanine or arginine, and a KRAS gene. The glycine acid encoded by codon 13 becomes a variation of aspartic acid.

於本說明書中使用之情形時，GST-π係指由GSTP1基因所編碼之對麩胱甘肽締合進行催化之酶。GST-π存在於包括人類在內之各種動 物體內，其序列資訊亦為公知(例如，人類：NM_000852(NP_000843)、大鼠：NM_012577(NP_036709)、小鼠：NM_013541(NP_038569)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將資料庫中所登記之人類GST-π基因之編碼區域之鹼基序列示於序列編號1，將該人類GST-π基因所編碼之人類GST-π蛋白質之胺基酸序列示於序列編號2。 As used in this specification, GST-π refers to an enzyme that catalyzes the association of glutathione encoded by the GSTP1 gene. GST-π exists in various movements including humans The sequence information is also known in the object (for example, human: NM_000852 (NP_000843), rat: NM_012577 (NP_036709), mouse: NM_013541 (NP_038569), etc.; the number indicates the registration number of the NCBI database, and the base sequence is outside the parentheses. The number in the parentheses is the number of the amino acid sequence). As an example, the base sequence of the coding region of the human GST-π gene registered in the database is shown in SEQ ID NO: 1, and the amino acid sequence of the human GST-π protein encoded by the human GST-π gene is shown in Sequence number 2.

於本說明書中使用之情形時，若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質於癌細胞係與單獨抑制GST-π時之致死率相比，於癌細胞中於與GST-π一併抑制時致死率顯著增大之蛋白質，且係具有與細胞之恆常性(恆定)相關之功能的蛋白質。此處，合成致死性稱為synthetic lethality，係指基因單獨缺損時不顯示針對細胞或個體之致死性或致死性較低，但若共存複數個基因缺損，則發揮出致死性或致死性顯著提高之現象。尤其於本說明書中，所謂合成致死性意指針對癌細胞之致死性。 When used in this specification, if it is inhibited together with GST-π, it shows that the lethality of the synthetic lethality maintains the related protein in the cancer cell line compared with the lethal rate when GST-π alone is inhibited. A protein in a cell that has a significantly increased lethality when combined with GST-π, and is a protein having a function related to the constant (constant) of cells. Here, synthetic lethality is called synthetic lethality, which means that the gene does not show a lethal or lethality against the cell or individual when the gene is alone, but if it coexists with multiple gene defects, it will play a significant increase in lethality or lethality. The phenomenon. Particularly in this specification, the so-called synthetic lethality is indicative of the lethality of cancer cells.

於本說明書中，作為若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質，例如可列舉：細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質。細胞週期調節蛋白質係具有調節細胞週期之功能之蛋白質。抗細胞凋亡相關蛋白質係具有抑制性地與細胞凋亡相關之功能的蛋白質。PI3K訊號傳遞路徑相關蛋白質係與PI3K/AKT訊號傳遞路徑相關之蛋白質中除Akt1以外之蛋白質。 In the present specification, as a constant-maintaining related protein which exhibits a synthetic lethality when it is inhibited together with GST-π, for example, a cell cycle-regulating protein, an anti-apoptosis-related protein, and a PI3K signal transmission pathway are involved. protein. Cell cycle regulatory proteins have proteins that regulate the function of the cell cycle. An anti-apoptosis-related protein has a protein that inhibits apoptosis-related functions. The PI3K signaling pathway-related protein is a protein other than Aktl in the protein associated with the PI3K/AKT signaling pathway.

又，所謂具有調節細胞週期之功能之蛋白質意指包括與包含G1期(DNA複製前之靜止期)、S期(DNA合成期)、G2(細胞分裂前之靜止期)及M期(細胞分裂期)之細胞週期相關之所有蛋白質。更具體而言，細胞週期之調節可列舉：按順序地進行G1期→S期→G2期→M期之機 構之調節、於G1期進行之對S期之進行調節及於G2期進行之對M期進行之調節之各項目。因此，細胞週期調節蛋白質可設為例如與細胞週期之該等項目之進行相關之蛋白質及將該等項目調節為正或負之蛋白質。更具體而言，作為細胞週期調節蛋白質，可列舉S期及M期之開始所必需之週期蛋白依賴性激酶(Cyclin-Dependent Kinase，CDK)等。週期蛋白依賴性激酶之活性係利用週期蛋白(Cyclin)之結合而調節為正。又，週期蛋白依賴性激酶之活性係利用p21(CIP1/WAF1)等週期蛋白依賴性激酶抑制因子(Cyclin-Dependent Kinase Inhibitor，CKI)及酪胺酸激酶而控制為負。因此，控制週期蛋白依賴性激酶之活性之該等週期蛋白、p21等週期蛋白依賴性激酶抑制因子及酪胺酸激酶亦包括於細胞週期調節蛋白質。 Further, the protein having a function of regulating the cell cycle is intended to include and include a G1 phase (a quiescent phase before DNA replication), a S phase (DNA synthesis phase), G2 (a quiescent phase before cell division), and a M phase (cell division). All proteins associated with the cell cycle. More specifically, the regulation of the cell cycle can be exemplified by sequentially performing the G1 phase→S phase→G2 phase→M phase. The adjustment of the structure, the adjustment of the S phase in the G1 phase, and the adjustment of the M phase in the G2 phase. Thus, the cell cycle regulatory protein can be, for example, a protein associated with the progression of such items in the cell cycle and a protein that regulates such items as positive or negative. More specifically, examples of the cell cycle regulating protein include Cyclin-Dependent Kinase (CDK) and the like which are necessary for the initiation of the S phase and the M phase. The activity of cyclin-dependent kinases is regulated positive by the binding of cyclin (Cyclin). Further, the activity of the cyclin-dependent kinase is controlled to be negative by using a Cyclin-Dependent Kinase Inhibitor (CKI) such as p21 (CIP1/WAF1) and tyrosine kinase. Therefore, such cyclins that control the activity of cyclin-dependent kinases, cyclin-dependent kinase inhibitors such as p21, and tyrosine kinases are also included in cell cycle regulatory proteins.

具體而言，作為若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質，可列舉：選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種細胞週期調節蛋白質。該等15種細胞週期調節蛋白質中，可將1種細胞週期調節蛋白質與GST-π一併加以抑制，亦可將2種以上細胞週期調節蛋白質與GST-π一併加以抑制。 Specifically, as a cell cycle-regulating protein which exhibits synthetic lethality when it is inhibited together with GST-π, it is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, and CENPH. At least one cell cycle regulatory protein of the group consisting of BRSK1, MCM8, CCNB3, MCMDC1, and MYLK. Among the 15 cell cycle regulatory proteins, one cell cycle regulatory protein can be inhibited together with GST-π, and two or more cell cycle regulatory proteins can be inhibited together with GST-π.

尤其是，作為細胞週期調節蛋白質，較佳為將選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種細胞週期調節蛋白質與GST-π一併加以抑制。該等6種細胞週期調節蛋白質於分別單獨抑制之情形時，細胞增殖抑制率相對較低，與GST-π一併抑制時首次顯示出顯著高之細胞增殖抑制效果。即，認為該等6種抑制細胞週期調節蛋白質之藥劑於單獨使用時安全性優異。因此，作為與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質，較佳為該等6種細胞週期調節蛋白質。 In particular, as the cell cycle regulating protein, at least one cell cycle regulating protein selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3, and MCMDC1 is preferably inhibited together with GST-π. When the six cell cycle regulatory proteins were inhibited separately, the cell proliferation inhibition rate was relatively low, and when combined with GST-π, the cell growth inhibition effect was markedly high for the first time. In other words, it is considered that these six kinds of agents for inhibiting cell cycle regulatory proteins are excellent in safety when used alone. Therefore, as a cell cycle-regulating protein which exhibits synthesis lethality when it is inhibited together with GST-π, it is preferable to use these six cell cycle-regulated proteins.

p21係屬於由CDKN1A基因所編碼之CIP/KIP家族之細胞週期調節蛋白質，其藉由與週期蛋白-CDK複合體結合而抑制複合體之作用，從而於G1期及G2/M期具有抑制細胞週期進行之作用。具體而言，p21係利用p53(癌抑制基因之一)而受到活化之基因，報告有若因DNA損傷等而使p53活化，則會活化p21，而於G1期及G2/M期使細胞週期停止。此外報告有，p21亦具有抑制細胞凋亡之功能，於活體外及動物試驗中，具有保護細胞而不發生由化學療法劑等所誘導之細胞凋亡的作用(Gartel and Tyner,2002；Abbs and Dutta,2009)。p21存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000389.4、NM_078467.2、NM_001291549.1、NM_001220778.1、NM_001220777.1(NP_001207707.1、NP_001278478.1、NP_001207706.1、NP_510867.1、NP_000380.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000389.4而登記於資料庫中之人類CDKN1A基因之鹼基序列示於序列編號3，將該人類CDKN1A基因所編碼之人p21蛋白質之胺基酸序列示於序列編號4。再者，於本說明書中，p21並不限定於包含由序列編號3之鹼基序列所編碼之序列編號4之胺基酸序列的蛋白質。關於p21，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號3之鹼基序列表示其中一個轉錄變異體之鹼基序列。 P21 belongs to the CIP/KIP family of cell cycle regulatory proteins encoded by the CDKN1A gene, which inhibits the action of the complex by binding to the cyclin-CDK complex, thereby inhibiting the cell cycle in the G1 phase and the G2/M phase. The role played. Specifically, p21 is a gene that is activated by p53 (one of the cancer suppressor genes), and it is reported that activation of p53 by DNA damage or the like activates p21, and causes cell cycle in G1 phase and G2/M phase. stop. In addition, it has been reported that p21 also has the function of inhibiting apoptosis, and in vitro and in animal experiments, it has the effect of protecting cells without apoptosis induced by chemotherapeutic agents (Gartel and Tyner, 2002; Abbs and Dutta, 2009). P21 is present in various animals including humans, and its sequence information is also known (for example, humans: NM_000389.4, NM_078467.2, NM_001291549.1, NM_001220778.1, NM_001220777.1 (NP_001207707.1, NP_001278478.1) , NP_001207706.1, NP_510867.1, NP_000380.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human CDKN1A gene registered as a NM_000389.4 in the database is shown in SEQ ID NO: 3, and the amino acid sequence of the human p21 protein encoded by the human CDKN1A gene is shown in SEQ ID NO: 4. Further, in the present specification, p21 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 4 encoded by the nucleotide sequence of SEQ ID NO: 3. Regarding p21, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 3 represents the base sequence of one of the transcribed variants.

RNPC1係由RNPC1基因所編碼之RNA結合蛋白質，係指成為p53之靶之蛋白質。RNPC1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_017495.5、NM_183425.2、NM_001291780.1、XM_005260446.1(XP_005260503.1、NP_059965.2、NP_906270.1、NP_001278709.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基酸序列，括號內為胺基酸序列之編 號)。作為一例，將作為NM_017495.5而登記於資料庫中之人類RNPC1基因之鹼基序列示於序列編號5，將該人類RNPC1基因所編碼之人類RNPC1蛋白質之胺基酸序列示於序列編號6。再者，於本說明書中，RNPC1並不限定於包含由序列編號5之鹼基序列所編碼之序列編號6之胺基酸序列的蛋白質。關於RNPC1，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號5之鹼基序列表示其中一個轉錄變異體之鹼基序列。 RNPC1 is an RNA-binding protein encoded by the RNPC1 gene, and refers to a protein that is a target of p53. RNPC1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_017495.5, NM_183425.2, NM_001291780.1, XM_005260446.1 (XP_005260503.1, NP_059965.2, NP_906270.1) , NP_001278709.1), etc.; the number indicates the registration number of the NCBI database, the base acid sequence outside the parentheses, and the amino acid sequence in parentheses number). As an example, the nucleotide sequence of the human RNPC1 gene which is registered in the database as NM_017495.5 is shown in SEQ ID NO: 5, and the amino acid sequence of the human RNPC1 protein encoded by the human RNPC1 gene is shown in SEQ ID NO: 6. Further, in the present specification, RNPC1 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 6 encoded by the nucleotide sequence of SEQ ID NO: 5. Regarding RNPC1, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 5 indicates the base sequence of one of the transcribed variants.

CCNL1係指由CCNL1基因所編碼之週期蛋白-L1。CCNL1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_020307.2、XM_005247647.2、XM_005247648.1、XM_005247649.1、XM_005247650.1、XM_005247651.1、XM_006713710.1、XM_006713711.1(XP_005247704.1、XP_005247705.1、XP_005247706.1、XP_005247707.1、XP_005247708.1、XP_006713773.1、NP_064703.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_020307.2而登記於資料庫中之人類CCNL1基因之鹼基序列示於序列編號7，將該人類CCNL1基因所編碼之人類CCNL1蛋白質之胺基酸序列示於序列編號8。再者，於本說明書中，CCNL1並不限定於包含由序列編號7之鹼基序列所編碼之序列編號8之胺基酸序列的蛋白質。關於CCNL1，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號7之鹼基序列表示其中一個轉錄變異體之鹼基序列。 CCNL1 refers to the cyclin-L1 encoded by the CCNL1 gene. CCNL1 is present in a variety of animals including humans, and its sequence information is also known (for example, humans: NM_020307.2, XM_005247647.2, XM_005247648.1, XM_005247649.1, XM_005247650.1, XM_005247651.1, XM_006713710.1) , XM_006713711.1 (XP_005247704.1, XP_005247705.1, XP_005247706.1, XP_005247707.1, XP_005247708.1, XP_006713773.1, NP_064703.1), etc.; the number indicates the registration number of the NCBI database, and the base sequence is outside the brackets. The number in the parentheses is the number of the amino acid sequence). As an example, the nucleotide sequence of the human CCNL1 gene registered in the database as NM_020307.2 is shown in SEQ ID NO: 7, and the amino acid sequence of the human CCNL1 protein encoded by the human CCNL1 gene is shown in SEQ ID NO: 8. Further, in the present specification, CCNL1 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 8 encoded by the nucleotide sequence of SEQ ID NO: 7. Regarding CCNL1, as described above, the sequence information is registered in a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 7 indicates the base sequence of one of the transcribed variants.

MCM8係指由MCM8基因所編碼之袖珍染色體維持蛋白質8(Mini-chromosome maintenance 8)。MCM8存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如人類：NM_032485.5、NM_182802.2、NM_001281520.1、NM_001281521.1、 NM_001281522.1、XM_005260859.1(XP_005260916.1、NP_115874.3、NP_001268449.1、NP_877954.1、NP_001268450.1、NP_001268451.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_032485.5而登記於資料庫中之人MCM8基因之鹼基序列示於序列編號9，將該人MCM8基因所編碼之人MCM8蛋白質之胺基酸序列示於序列編號10。再者，於本說明書中，MCM8並不限定於包含由序列編號9之鹼基序列所編碼之序列編號10之胺基酸序列的蛋白質。關於MCM8，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號9之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MCM8 refers to Mini-chromosome maintenance 8 encoded by the MCM8 gene. MCM8 is present in various animals including humans, and its sequence information is also known (for example, humans: NM_032485.5, NM_182802.2, NM_001281520.1, NM_001281521.1, NM_001281522.1, XM_005260859.1 (XP_005260916.1, NP_115874.3, NP_001268449.1, NP_877954.1, NP_001268450.1, NP_001268451.1), etc.; the number indicates the registration number of the NCBI database, and the base sequence is outside the brackets. The number of the amino acid sequence is within). As an example, the nucleotide sequence of the human MCM8 gene registered as a NM_032485.5 in the database is shown in SEQ ID NO: 9, and the amino acid sequence of the human MCM8 protein encoded by the human MCM8 gene is shown in SEQ ID NO: 10. Further, in the present specification, MCM8 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 10 encoded by the nucleotide sequence of SEQ ID NO: 9. Regarding the MCM 8, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 9 indicates the base sequence of one of the transcribed variants.

CCNB3係指由CCNB3基因所編碼之週期蛋白-B3。CCNB3存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_033670.2、NM_033031.2、XM_006724610.1(NP_391990.1、NP_149020.2、XP_006724673.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_033670.2而登記於資料庫中之人類CCNB3基因之鹼基序列示於序列編號11，將該人類CCNB3基因所編碼之人類CCNB3蛋白質之胺基酸序列示於序列編號12。再者，於本說明書中，CCNB3並不限定於包含由序列編號11之鹼基序列所編碼之序列編號12之胺基酸序列的蛋白質。關於CCNB3，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號11之鹼基序列表示其中一個轉錄變異體之鹼基序列。 CCNB3 refers to cyclin-B3 encoded by the CCNB3 gene. CCNB3 is present in various animals including humans, and its sequence information is also known (for example, human: NM_033670.2, NM_033031.2, XM_006724610.1 (NP_391990.1, NP_149020.2, XP_006724673.1), etc.; Indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human CCNB3 gene which is registered in the database as NM_033670.2 is shown in SEQ ID NO: 11, and the amino acid sequence of the human CCNB3 protein encoded by the human CCNB3 gene is shown in SEQ ID NO: 12. Further, in the present specification, CCNB3 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 12 encoded by the nucleotide sequence of SEQ ID NO: 11. Regarding CCNB3, as described above, the sequence information is registered in a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 11 indicates the base sequence of one of the transcribed variants.

MCMDC1係指由MCMDC1基因所編碼之袖珍染色體維持缺損區域1(Mini-chromosome maintenance deficient domain containing 1)。MCMDC1存在於包括人類在內之各種動物體內，其序列資訊亦為公 知(例如，人類：NM_017696.2、NM_153255.4(NP_060166.2、NP_694987.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_017696.2而登記於資料庫中之人類MCMDC1基因之鹼基序列示於序列編號13，將該人類MCMDC1基因所編碼之人類MCMDC1蛋白質之胺基酸序列示於序列編號14。再者，於本說明書中，MCMDC1並不限定於包含由序列編號13之鹼基序列所編碼之序列編號14之胺基酸序列的蛋白質。關於MCMDC1，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號13之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MCMDC1 refers to the Mini-chromosome maintenance deficient domain containing 1 encoded by the MCMDC1 gene. MCMDC1 exists in various animals including humans, and its sequence information is also public. Know (for example, human: NM_017696.2, NM_153255.4 (NP_060166.2, NP_694987.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human MCMDC1 gene registered in the database as NM_017696.2 is shown in SEQ ID NO: 13, and the amino acid sequence of the human MCMDC1 protein encoded by the human MCMDC1 gene is shown in SEQ ID NO: 14. Further, in the present specification, MCMDC1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 14 encoded by the nucleotide sequence of SEQ ID NO: 13. Regarding MCMDC1, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 13 indicates the base sequence of one of the transcribed variants.

ATM係由ATM基因所編碼之ATM絲胺酸/蘇胺酸磷酸化酶(ATM Serine/Threonine Kinase)，係指屬於PI3/PI4磷酸化酶家族之蛋白質。ATM存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000051.3、XM_005271561.2、XM_005271562.2、XM_005271564.2、XM_006718843.1、XM_006718844.1、XM_006718845.1(NP_000042.3、XP_005271618.2、XP_005271619.2、XP_005271621.2、XP_006718906.1、XP_006718907.1、XP_006718908.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000051.3而登記於資料庫中之人類ATM基因之鹼基序列示於序列編號15，將該人類ATM基因所編碼之人類ATM蛋白質之胺基酸序列示於序列編號16。再者，於本說明書中，ATM並不限定於包含由序列編號15之鹼基序列所編碼之序列編號16之胺基酸序列的蛋白質。關於ATM，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號15之鹼基序列表示其中一個轉錄變異體之鹼基序列。 ATM is an ATM Serine/Threonine Kinase encoded by the ATM gene, and refers to a protein belonging to the PI3/PI4 phosphorylase family. ATM exists in various animals including humans, and its sequence information is also known (for example, human: NM_000051.3, XM_005271561.2, XM_005271562.2, XM_005271564.2, XM_006718843.1, XM_006718844.1, XM_006718845.1) (NP_000042.3, XP_005271618.2, XP_005271619.2, XP_005271621.2, XP_006718906.1, XP_006718907.1, XP_006718908.1), etc.; the number indicates the registration number of the NCBI database, the base sequence is outside the parentheses, and the amine is in parentheses. The number of the base acid sequence). As an example, the nucleotide sequence of the human ATM gene registered as a NM_000051.3 in the database is shown in SEQ ID NO: 15, and the amino acid sequence of the human ATM protein encoded by the human ATM gene is shown in SEQ ID NO: 16. Further, in the present specification, the ATM is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 16 encoded by the nucleotide sequence of SEQ ID NO: 15. Regarding the ATM, as described above, the sequence information is registered in a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 15 indicates the base sequence of one of the transcribed variants.

CDC25A係指屬於由CDC25A基因所編碼之CDC25家族之脫磷酸化酶，且係藉由將CDC2脫磷酸化而活化之蛋白質。CDC25A存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001789.2、NM_201567.1、XM_006713434.1、XM_006713435.1、XM_006713436.1(NP_001780.2、NP_963861.1、XP_006713497.1、XP_006713498.1、XP_006713499.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001789.2而登記於資料庫中之人類CDC25A基因之鹼基序列示於序列編號17，將該人類CDC25A基因所編碼之人類CDC25A蛋白質之胺基酸序列示於序列編號18。再者，於本說明書中，CDC25A並不限定於包含由序列編號17之鹼基序列所編碼之序列編號18之胺基酸序列的蛋白質。關於CDC25A，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號17之鹼基序列表示其中一個轉錄變異體之鹼基序列。 CDC25A refers to a protein belonging to the CDC25 family of dephosphorylation enzymes encoded by the CDC25A gene and which is activated by dephosphorylation of CDC2. CDC25A is present in a variety of animals including humans, and its sequence information is also known (for example, humans: NM_001789.2, NM_201567.1, XM_006713434.1, XM_006713435.1, XM_006713436.1 (NP_001780.2, NP_963861.1) , XP_006713497.1, XP_006713498.1, XP_006713499.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human CDC25A gene which is registered in the database as NM_001789.2 is shown in SEQ ID NO: 17, and the amino acid sequence of the human CDC25A protein encoded by the human CDC25A gene is shown in SEQ ID NO: 18. Further, in the present specification, CDC25A is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 18 encoded by the nucleotide sequence of SEQ ID NO: 17. Regarding the CDC 25A, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 17 indicates the base sequence of one of the transcribed variants.

PRKDC係由PRKDC基因所編碼之DNA依賴性蛋白質磷酸化酶(DNA-dependent Protein Kinase)之觸媒次單元蛋白質，係指屬於PI3/PI4磷酸化酶家族之蛋白質。PRKDC存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_006904.6、NM_001081640.1(NP_008835.5、NP_001075109.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基酸序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_006904.6而登記於資料庫中之人類PRKDC基因之鹼基序列示於序列編號19，將該人類PRKDC基因所編碼之人類PRKDC蛋白質之胺基酸序列示於序列編號20。再者，於本說明書中，PRKDC並不限定於包含由序列編號19之鹼基序列所編碼之序列編號20之胺基酸序列的蛋白質。關於PRKDC，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號19 之鹼基序列表示其中一個轉錄變異體之鹼基序列。 PRKDC is a catalytic subunit protein of DNA-dependent Protein Kinase encoded by the PRKDC gene, and refers to a protein belonging to the PI3/PI4 phosphorylase family. PRKDC is present in various animals including humans, and its sequence information is also known (for example, human: NM_006904.6, NM_001081640.1 (NP_008835.5, NP_001075109.1), etc.; the number indicates the registration number of the NCBI database, The base acid sequence outside the parentheses is the number of the amino acid sequence in parentheses. As an example, the nucleotide sequence of the human PRKDC gene registered in the database as NM_006904.6 is shown in SEQ ID NO: 19, and the amino acid sequence of the human PRKDC protein encoded by the human PRKDC gene is shown in SEQ ID NO: 20. Further, in the present specification, PRKDC is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 20 encoded by the nucleotide sequence of SEQ ID NO: 19. Regarding PRKDC, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. Sequence number 19 The base sequence represents the base sequence of one of the transcriptional variants.

RBBP8係由RBBP8基因所編碼之視網膜胚細胞膜結合蛋白質8(Retinoblastoma Binding Protein 8)，係指與視網膜胚細胞膜蛋白質直接結合之核內蛋白質。RBBP8存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_002894.2、NM_203291.1、NM_203292.1、XM_005258325.1、XM_005258326.1、XM_006722519.1、XM_006722520.1、XM_006722521.1、XM_006722522.1(NP_002885.1、NP_976036.1、NP_976037.1、XP_005258382.1、XP_005258383.1、XP_006722582.1、XP_006722583.1、XP_006722584.1、XP_006722585.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_002894.2而登記於資料庫中之人類RBBP8基因之鹼基序列示於序列編號21，將該人類RBBP8基因所編碼之人類RBBP8蛋白質之胺基酸序列示於序列編號22。再者，於本說明書中，RBBP8並不限定於包含由序列編號21之鹼基序列所編碼之序列編號22之胺基酸序列的蛋白質。關於RBBP8，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號21之鹼基序列表示其中一個轉錄變異體之鹼基序列。 RBBP8 is a retinoblastoma binding protein 8 (Retinoblastoma Binding Protein 8) encoded by the RBBP8 gene, and refers to a nuclear protein that directly binds to the retinoblast membrane protein. RBBP8 is present in a variety of animals including humans, and its sequence information is also known (for example, humans: NM_002894.2, NM_203291.1, NM_203292.1, XM_005258325.1, XM_005258326.1, XM_006722519.1, XM_006722520.1) , XM_006722521.1, XM_006722522.1 (NP_002885.1, NP_976036.1, NP_976037.1, XP_005258382.1, XP_005258383.1, XP_006722582.1, XP_006722583.1, XP_006722584.1, XP_006722585.1), etc.; The registration number of the database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human RBBP8 gene registered in the database as NM_002894.2 is shown in SEQ ID NO: 21, and the amino acid sequence of the human RBBP8 protein encoded by the human RBBP8 gene is shown in SEQ ID NO: 22. Further, in the present specification, RBBP8 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 22 encoded by the nucleotide sequence of SEQ ID NO: 21. Regarding RBBP8, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 21 represents the base sequence of one of the transcribed variants.

SKP2係由SKP2基因所編碼之S期激酶相關蛋白質(S-phase Kinase-associated Protein 2)，係指E3泛蛋白蛋白質連接酶之4次單元之一的屬於Fbox蛋白質之蛋白質。SKP2存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如人類：NM_005983.3、NM_032637.3、NM_001243120.1、XM_006714487.1(NP_005974.2、NP_116026.1、NP_001230049.1、XP_006714550.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列 之編號)。作為一例，將作為NM_005983.3而登記於資料庫中之人類SKP2基因之編碼區域之鹼基序列示於序列編號23，將該人類SKP2基因所編碼之人類SKP2蛋白質之胺基酸序列示於序列編號24。再者，於本說明書中，SKP2並不限定於包含由序列編號23之鹼基序列所編碼之序列編號24之胺基酸序列的蛋白質。關於SKP2，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號23之鹼基序列表示其中一個轉錄變異體之鹼基序列。 SKP2 is a S-phase Kinase-associated Protein 2 encoded by the SKP2 gene, and is a protein belonging to the Fbox protein which is one of the fourth-order units of the E3 ubiquitin protein ligase. SKP2 is present in a variety of animals, including humans, and its sequence information is also well known (eg human: NM_005983.3, NM_032637.3, NM_001243120.1, XM_006714487.1 (NP_005974.2, NP_116026.1, NP_001230049.1, XP_006714550.1), etc.; the number indicates the registration number of the NCBI database, the base sequence is outside the parentheses, and the amino acid sequence is in parentheses. Number). As an example, the nucleotide sequence of the coding region of the human SKP2 gene registered as a NM_005983.3 in the database is shown in SEQ ID NO: 23, and the amino acid sequence of the human SKP2 protein encoded by the human SKP2 gene is shown in the sequence. No. 24. Further, in the present specification, SKP2 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 24 encoded by the nucleotide sequence of SEQ ID NO: 23. Regarding SKP2, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 23 represents the base sequence of one of the transcribed variants.

MCM10係指由MCM10基因所編碼之袖珍染色體維持蛋白質10(Mini-Chromosome Maintenance 10)。MCM10存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_182751.2、NM_018518.4(NP_877428.1、NP_060988.3)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_182751.2而登記於資料庫中之人類MCM10基因之鹼基序列示於序列編號25，將該人類MCM10基因所編碼之人類MCM10蛋白質之胺基酸序列示於序列編號26。再者，於本說明書中，MCM10並不限定於包含由序列編號25之鹼基序列所編碼之序列編號26之胺基酸序列的蛋白質。關於MCM10，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號25之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MCM10 refers to Mini-Chromosome Maintenance 10 encoded by the MCM10 gene. MCM10 is present in various animals including humans, and its sequence information is also known (for example, human: NM_182751.2, NM_018518.4 (NP_877428.1, NP_060988.3), etc.; the number indicates the registration number of the NCBI database, The base sequence is outside the parentheses, and the amino acid sequence number is in parentheses. As an example, the nucleotide sequence of the human MCM10 gene which is registered in the database as NM_182751.2 is shown in SEQ ID NO:25, and the amino acid sequence of the human MCM10 protein encoded by the human MCM10 gene is shown in SEQ ID NO:26. Further, in the present specification, MCM10 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 26 encoded by the nucleotide sequence of SEQ ID NO: 25. Regarding the MCM 10, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 25 represents the base sequence of one of the transcribed variants.

CENPH係指由CENPH基因所編碼之中節蛋白質H(Centromere Protein H)，構成配置於中節上之活化著絲點的蛋白質之一。CENPH存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_022909.3(NP_075060.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_022909.3而登記於資料庫中之人類CENPH基因之鹼基序列示於序列編號27，將該人類CENPH基因所編碼之人類CENPH蛋 白質之胺基酸序列示於序列編號28。再者，於本說明書中，CENPH並不限定於包含由序列編號27之鹼基序列所編碼之序列編號28之胺基酸序列的蛋白質。關於CENPH，有存在複數個轉錄變異體之可能性。序列編號27之鹼基序列表示一個轉錄變異體之鹼基序列。 CENPH refers to one of the proteins that are encoded by the CENPH gene, Centromere Protein H, which constitutes the activated centromere located on the middle segment. CENPH is present in various animals including humans, and its sequence information is also known (for example, human: NM_022909.3 (NP_075060.1); etc.; the number indicates the registration number of the NCBI database, and the base sequence is in parentheses. Is the number of the amino acid sequence). As an example, the base sequence of the human CENPH gene registered as a NM_022909.3 in the database is shown in SEQ ID NO: 27, and the human CENPH egg encoded by the human CENPH gene is shown. The amino acid sequence of the white matter is shown in SEQ ID NO: 28. Further, in the present specification, CENPH is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 28 encoded by the nucleotide sequence of SEQ ID NO: 27. With regard to CENPH, there are possibilities for the presence of multiple transcriptional variants. The nucleotide sequence of SEQ ID NO: 27 represents the base sequence of a transcribed variant.

BRSK1係由BRSK1基因所編碼之絲胺酸/蘇胺酸磷酸化酶，且係作用於DNA損傷中之細胞週期檢測點的磷酸化酶。BRSK1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_032430.1、XM_005259327.1、XR_430213.1(NP_115806.1、XP_005259384.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_032430.1而登記於資料庫中之人類BRSK1基因之鹼基序列示於序列編號29，將該人類BRSK1基因所編碼之人類BRSK1蛋白質之胺基酸序列示於序列編號30。再者，於本說明書中，BRSK1並不限定於包含由序列編號29之鹼基序列所編碼之序列編號30之胺基酸序列的蛋白質。關於BRSK1，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號29之鹼基序列表示其中一個轉錄變異體之鹼基序列。 BRSK1 is a serine/threonine phosphorylase encoded by the BRSK1 gene and acts as a phosphorylase at the cell cycle checkpoint in DNA damage. BRSK1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_032430.1, XM_005259327.1, XR_430213.1 (NP_115806.1, XP_005259384.1), etc.; number indicates NCBI database The registration number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human BRSK1 gene registered in the database as NM_032430.1 is shown in SEQ ID NO:29, and the amino acid sequence of the human BRSK1 protein encoded by the human BRSK1 gene is shown in SEQ ID NO:30. Further, in the present specification, BRSK1 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 30 encoded by the nucleotide sequence of SEQ ID NO:29. Regarding BRSK1, as described above, the sequence information is registered in a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 29 represents the base sequence of one of the transcribed variants.

MYLK(myosin light chain kinase，肌球蛋白輕鏈激酶)係鈣/鈣調蛋白依賴性酶之肌球蛋白輕鏈激酶，其將肌球蛋白控制輕鏈進行磷酸化，促進肌球蛋白與肌動蛋白纖維之相互作用，而產生收縮活動。編碼MYLK之基因編碼平滑肌及非肌肉性isodome之兩者。MYLK存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_053028.3,NM_053026.3,NM_053027.3,NM_053025.3,NM_053031.2,NM_053032.2,XM_011512862.1,XM_011512861.1,XM_011512860.1(NP_444256.3,NP_444254.3,NP_444255.3,NP_444253.3,NP_444259.1,NP_444260.1,XP_011511164.1, XP_011511163.1,XP_011511162.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_053028.3而登記於資料庫中之人類MYLK基因之鹼基序列示於序列編號41，將該人類MYLK基因所編碼之人類MYLK蛋白質之胺基酸序列示於序列編號42。再者，於本說明書中，MYLK並不限定於包含由序列編號41之鹼基序列所編碼之序列編號42之胺基酸序列的蛋白質。關於MYLK，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號41之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MYLK (myosin light chain kinase) is a calcium/calmodulin-dependent enzyme myosin light chain kinase that phosphorylates myosin-controlled light chain and promotes myosin and muscle movement The interaction of protein fibers produces contractile activity. The gene encoding MYLK encodes both smooth muscle and non-muscle isodome. MYLK is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_053028.3, NM_053026.3, NM_053027.3, NM_053025.3, NM_053031.2, NM_053032.2, XM_011512862.1 , XM_011512861.1, XM_011512860.1 (NP_444256.3, NP_444254.3, NP_444255.3, NP_444253.3, NP_444259.1, NP_444260.1, XP_011511164.1, XP_011511163.1, XP_011511162.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human MYLK gene registered as a NM_053028.3 in the database is shown in SEQ ID NO: 41, and the amino acid sequence of the human MYLK protein encoded by the human MYLK gene is shown in SEQ ID NO: 42. Further, in the present specification, MYLK is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 42 encoded by the nucleotide sequence of SEQ ID NO:41. Regarding MYLK, as described above, the sequence information is registered in a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 41 represents the base sequence of one of the transcribed variants.

另一方面，具有抑制性地與細胞凋亡相關之功能之蛋白質係藉由抑制核凝集、細胞收縮、膜皰形成及DNA之片段化等之機制而具有抑制細胞凋亡之功能的蛋白質。所謂抑制性地與細胞凋亡相關之功能意指包括抑制細胞凋亡之功能及抑制促進細胞凋亡之因子之功能之任一者。作為促進細胞凋亡之因子，例如可列舉：半胱天冬酶或Fas、TNFR等諸多因子。 On the other hand, a protein having a function of inhibiting apoptosis is a protein having a function of inhibiting apoptosis by inhibiting mechanisms such as nuclear agglutination, cell contraction, blister formation, and fragmentation of DNA. The function of inhibiting apoptosis-related functions means any one of a function of inhibiting apoptosis and a function of inhibiting a factor of promoting apoptosis. Examples of the factor for promoting apoptosis include caspase, Fas, and TNFR.

具體而言，作為若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質，可列舉選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。該等20種抗細胞凋亡相關蛋白質中，可將1種抗細胞凋亡相關蛋白質與GST-π一併加以抑制，亦可將2種以上抗細胞凋亡相關蛋白質與GST-π一併加以抑制。 Specifically, as an anti-apoptosis-related protein which exhibits a synthetic lethality when it is inhibited together with GST-π, it is selected from AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1. At least one anti-apoptosis-related protein of a group consisting of BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A. Among the 20 anti-apoptosis-related proteins, one anti-apoptosis-related protein can be inhibited together with GST-π, and two or more anti-apoptosis-related proteins can be combined with GST-π. inhibition.

AATF被鑑定為與和細胞凋亡相關之蛋白激酶MAP3K12/DLK相互作用者。AATF包含作為轉錄因子之特徵性結構的白胺酸拉鏈，於與Gal4 DNA結合區域融合時顯示出引起較強轉錄活化之情況。又， 已知藉由編碼AATF之基因之過度表現，會抑制MAP3K12誘導性之細胞凋亡。AATF存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_012138.3,XM_011546799.1,XM_011524611.1,XR_951958.1,XR_934439.1(NP_036270.1,XP_011545101.1,XP_011522913.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_012138.3而登記於資料庫中之人類AATF基因之鹼基序列示於序列編號39，將該人類AATF基因所編碼之人類AATF蛋白質之胺基酸序列示於序列編號40。再者，於本說明書中，AATF並不限定於包含由序列編號39之鹼基序列所編碼之序列編號40之胺基酸序列的蛋白質。關於AATF，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號39之鹼基序列表示其中一個轉錄變異體之鹼基序列。 AATF was identified as a protein kinase MAP3K12/DLK interactor associated with apoptosis. AATF contains a leucine zipper which is a characteristic structure of a transcription factor and exhibits a strong transcriptional activation when fused to a Gal4 DNA-binding region. also, It is known that MAP3K12-induced apoptosis is inhibited by overexpression of a gene encoding AATF. AATF is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_012138.3, XM_011546799.1, XM_011524611.1, XR_951958.1, XR_934439.1 (NP_036270.1, XP_011545101.1) , XP_011522913.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human AATF gene registered as a NM_012138.3 in the database is shown in SEQ ID NO: 39, and the amino acid sequence of the human AATF protein encoded by the human AATF gene is shown in SEQ ID NO: 40. Further, in the present specification, the AATF is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 40 encoded by the nucleotide sequence of SEQ ID NO: 39. Regarding the AATF, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 39 indicates the base sequence of one of the transcribed variants.

ALOX12係花生四烯酸-12-脂肪加氧酶，已知其與動脈粥狀硬化或骨質疏鬆症等相關。已知ALOX12藉由控制血管內皮增殖因子之表現而將血管形成控制為正，促進血管平滑肌細胞等之存活而與細胞凋亡進程相關。ALOX12存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000697.2,XM_011523780.1(NP_000688.2,XP_011522082.1,AAH69557.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000697.2而登記於資料庫中之人類ALOX12基因之鹼基序列示於序列編號43，將該人類ALOX12基因所編碼之人類ALOX12蛋白質之胺基酸序列示於序列編號44。再者，於本說明書中，ALOX12並不限定於包含由序列編號43之鹼基序列所編碼之序列編號44之胺基酸序列的蛋白質。關於ALOX12，如上所述，以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序 列編號43之鹼基序列表示其中一個轉錄變異體之鹼基序列。 ALOX12 is an arachidonic acid-12-lipoxygenase which is known to be associated with atherosclerosis or osteoporosis. It is known that ALOX12 controls vascular formation to be positive by controlling the expression of vascular endothelial growth factor, and promotes survival of vascular smooth muscle cells and the like in association with apoptosis progress. ALOX12 is present in various animals including humans, and its sequence information is also known (for example, human: NM_000697.2, XM_011523780.1 (NP_000688.2, XP_011522082.1, AAH69557.1), etc.; number indicates NCBI database The registration number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human ALOX12 gene which is registered in the database as NM_000697.2 is shown in SEQ ID NO: 43, and the amino acid sequence of the human ALOX12 protein encoded by the human ALOX12 gene is shown in SEQ ID NO: 44. Further, in the present specification, ALOX12 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 44 encoded by the nucleotide sequence of SEQ ID NO: 43. Regarding ALOX12, as described above, the sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. sequence The nucleotide sequence of column number 43 indicates the base sequence of one of the transcription variants.

ANXA1係與磷脂質結合之膜局部存在蛋白質。ANXA1抑制磷脂酶A2，具有抗炎症活性。ANXA1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000700.2,XM_011518609.1,XM_011518608.1(NP_000691.1,AAH34157.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000700.2而登記於資料庫中之人類ANXA1基因之鹼基序列示於序列編號45，將該人類ANXA1基因所編碼之人類ANXA1蛋白質之胺基酸序列示於序列編號46。再者，於本說明書中，ANXA1並不限定於包含由序列編號45之鹼基序列所編碼之序列編號46之胺基酸序列的蛋白質。關於ANXA1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號45之鹼基序列表示其中一個轉錄變異體之鹼基序列。 ANXA1 is a protein localized in the membrane bound to phospholipids. ANXA1 inhibits phospholipase A2 and has anti-inflammatory activity. ANXA1 is present in a variety of animals including humans, and its sequence information is also known (for example, human: NM_000700.2, XM_011518609.1, XM_011518608.1 (NP_000691.1, AAH34157.1), etc.; number indicates NCBI database The registration number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human ANXA1 gene which is registered in the database as NM_000700.2 is shown in SEQ ID NO: 45, and the amino acid sequence of the human ANXA1 protein encoded by the human ANXA1 gene is shown in SEQ ID NO: 46. Further, in the present specification, ANXA1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 46 encoded by the nucleotide sequence of SEQ ID NO: 45. Regarding ANXA1, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 45 indicates the base sequence of one of the transcribed variants.

已知ANXA4屬於作為鈣依賴性磷脂質結合性蛋白質之膜聯蛋白家族，有與ATP相互作用之可能性，於活體外顯示出抗凝活性，抑制磷脂酶A2。ANXA4存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001153.3,XM_011532805.1(NP_001144.1,XP_011531107.1,AAH63672.1,AAH00182.1,AAH11659.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001153.3而登記於資料庫中之人類ANXA4基因之鹼基序列示於序列編號47，將該人類ANXA4基因所編碼之人類ANXA4蛋白質之胺基酸序列示於序列編號48。再者，於本說明書中，ANXA4並不限定於包含由序列編號47之鹼基序列所編碼之序列編號48之胺基酸序列的蛋白質。關於ANXA4，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號47之鹼基序列表示其中一個轉錄變異 體之鹼基序列。 ANXA4 is known to belong to the annexin family, which is a calcium-dependent phospholipid-binding protein, and has the possibility of interacting with ATP, exhibiting anticoagulant activity in vitro and inhibiting phospholipase A2. ANXA4 is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_001153.3, XM_011532805.1 (NP_001144.1, XP_011531107.1, AAH63672.1, AAH00182.1, AAH11659.1) ); the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human ANXA4 gene which is registered in the database as NM_001153.3 is shown in SEQ ID NO: 47, and the amino acid sequence of the human ANXA4 protein encoded by the human ANXA4 gene is shown in SEQ ID NO: 48. Further, in the present specification, ANXA4 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 48 encoded by the nucleotide sequence of SEQ ID NO:47. Regarding ANXA4, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The base sequence of SEQ ID NO: 47 indicates one of the transcriptional variations The base sequence of the body.

已知API5係細胞凋亡抑制蛋白質，藉由其之表現而於缺乏成長因子缺後停止細胞凋亡。API5抑制轉錄因子E2F1誘導性細胞凋亡，其與和細胞凋亡中之DNA片段化相關之核因子的腺泡(Acinus)相互作用，而將其控制為負。API5存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001142930.1,NM_006595.3,NM_001243747.1,NM_001142931.1,XM_006718359.2,NR_024625.1(NP_001136402.1,NP_001136403.1,NP_001230676.1,NP_006586.1,XP_006718422.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001142930.1而登記於資料庫中之人類API5基因之鹼基序列示於序列編號49，將該人類API5基因所編碼之人類API5蛋白質之胺基酸序列示於序列編號50。再者，於本說明書中，API5並不限定於包含由序列編號49之鹼基序列所編碼之序列編號50之胺基酸序列的蛋白質。關於API5，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號49之鹼基序列表示其中一個轉錄變異體之鹼基序列。 It is known that API5 is an apoptosis-inhibiting protein, and its expression is such that apoptosis is stopped in the absence of growth factor deficiency. API5 inhibits the transcription factor E2F1-induced apoptosis, which interacts with the acinus (Acinus) of the nuclear factor involved in DNA fragmentation in apoptosis, and controls it to be negative. API5 is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_001142930.1, NM_006595.3, NM_001243747.1, NM_001142931.1, XM_006718359.2, NR_024625.1 (NP_001136402.1) , NP_001136403.1, NP_001230676.1, NP_006586.1, XP_006718422.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human API5 gene registered as a NM_001142930.1 in the database is shown in SEQ ID NO: 49, and the amino acid sequence of the human API5 protein encoded by the human API5 gene is shown in SEQ ID NO: 50. Further, in the present specification, the API 5 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 50 encoded by the nucleotide sequence of SEQ ID NO: 49. Regarding API5, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 49 indicates the base sequence of one of the transcribed variants.

已知ATF5係與由人類T細胞白血病1型病毒所致之疾病相關。已知ATF5係存在於諸多病毒啟動子等中之與cAMP應答元件(CRE)結合之轉錄活化因子，其抑制自神經前驅細胞向神經元之分化。ATF5存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_012068.5,NM_001193646.1,NM_001290746.1,XM_011526629.1(NP_036200.2,NP_001277675.1,NP_001180575.1,XP_011524931.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_012068.5而登記於資料庫中之人類ATF5基因之鹼基序列示於序列 編號51，將該人類ATF5基因所編碼之人類ATF5蛋白質之胺基酸序列示於序列編號52。再者，於本說明書中，ATF5並不限定於包含由序列編號51之鹼基序列所編碼之序列編號52之胺基酸序列的蛋白質。關於ATF5，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號51之鹼基序列表示其中一個轉錄變異體之鹼基序列。 The ATF5 line is known to be associated with diseases caused by human T cell leukemia type 1 virus. ATF5 is known to be a transcriptional activator that binds to a cAMP response element (CRE) in many viral promoters and the like, and inhibits differentiation from neural precursor cells to neurons. ATF5 is present in various animals including humans, and its sequence information is also known (for example, human: NM_012068.5, NM_001193646.1, NM_001290746.1, XM_011526629.1 (NP_036200.2, NP_001277675.1, NP_001180575.1) , XP_011524931.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the base sequence of the human ATF5 gene registered as a NM_012068.5 in the database is shown in the sequence. No. 51, the amino acid sequence of the human ATF5 protein encoded by the human ATF5 gene is shown in SEQ ID NO:52. Further, in the present specification, ATF5 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 52 encoded by the nucleotide sequence of SEQ ID NO: 51. Regarding ATF 5, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 51 indicates the base sequence of one of the transcribed variants.

已知AVEN係作為細胞凋亡、半胱天冬酶活化抑制因子而已知之蛋白質，其與類分裂性人格障礙或述情障礙。已知AVEN抑制經由Apaf1引起之細胞凋亡。AVEN存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_020371.2,XM_011521820.1,XM_005254563.2,XM_011521819.1,XM_011521818.1(NP NP_065104.1,XP_011520122.1,XP_011520121.1,XP_011520120.1,XP_005254620.1,AAH63533.1,AAF91470.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_020371.2而登記於資料庫中之人類AVEN基因之鹼基序列示於序列編號53，將該人類AVEN基因所編碼之人類AVEN蛋白質之胺基酸序列示於序列編號54。再者，於本說明書中，AVEN並不限定於包含由序列編號53之鹼基序列所編碼之序列編號54之胺基酸序列的蛋白質。關於AVEN，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號53之鹼基序列表示其中一個轉錄變異體之鹼基序列。 AVEN is known as a protein known as apoptosis, a caspase activation inhibitor, and a mitotic personality disorder or autism disorder. AVEN is known to inhibit apoptosis induced by Apaf1. AVEN is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_020371.2, XM_011521820.1, XM_005254563.2, XM_011521819.1, XM_011521818.1 (NP NP_065104.1, XP_011520122. 1, XP_011520121.1, XP_011520120.1, XP_005254620.1, AAH63533.1, AAF91470.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human AVEN gene which is registered in the database as NM_020371.2 is shown in SEQ ID NO: 53, and the amino acid sequence of the human AVEN protein encoded by the human AVEN gene is shown in SEQ ID NO: 54. Further, in the present specification, AVEN is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 54 encoded by the nucleotide sequence of SEQ ID NO: 53. Regarding AVEN, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 53 indicates the base sequence of one of the transcribed variants.

AZU1係包含於藍色顆粒中之蛋白質，具有單核球趨化及抗菌活性。AZU1係重要之多功能炎症性媒介物。AZU1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001700.3(NP_001691.1,EAW69592.1,AAH93933.1,AAH93931.1,AAH69495.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序 列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001700.3而登記於資料庫中之人類AZU1基因之鹼基序列示於序列編號55，將該人類AZU1基因所編碼之人類AZU1蛋白質之胺基酸序列示於序列編號56。再者，於本說明書中，AZU1並不限定於包含由序列編號55之鹼基序列所編碼之序列編號56之胺基酸序列的蛋白質。關於AZU1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號55之鹼基序列表示其中一個轉錄變異體之鹼基序列。 AZU1 is a protein contained in blue particles and has mononuclear ball chemotaxis and antibacterial activity. AZU1 is an important multifunctional inflammatory vehicle. AZU1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_001700.3 (NP_001691.1, EAW69592.1, AAH93933.1, AAH93931.1, AAH69495.1), etc.; Indicates the registration number of the NCBI database, and the base order outside the parentheses Column, in parentheses is the number of the amino acid sequence). As an example, the nucleotide sequence of the human AZU1 gene registered as a NM_001700.3 in the database is shown in SEQ ID NO: 55, and the amino acid sequence of the human AZU1 protein encoded by the human AZU1 gene is shown in SEQ ID NO: 56. Further, in the present specification, AZU1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 56 encoded by the nucleotide sequence of SEQ ID NO: 55. Regarding AZU1, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 55 indicates the base sequence of one of the transcribed variants.

BAG1係與作為抑制誘導細胞凋亡或程式細胞死亡之路徑之膜蛋白質的BCL2結合。BAG1係增強BCL2之抗細胞凋亡作用，表示增殖因子受體與抗細胞凋亡機制之間之聯繫。BAG1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_004323.5,NM_001172415.1(NP_004314.5,NP_001165886.1,AAH14774.2)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_004323.5而登記於資料庫中之人類BAG1基因之鹼基序列示於序列編號57，將該人類BAG1基因所編碼之人類BAG1蛋白質之胺基酸序列示於序列編號58。再者，於本說明書中，BAG1並不限定於包含由序列編號57之鹼基序列所編碼之序列編號58之胺基酸序列的蛋白質。關於BAG1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號57之鹼基序列表示其中一個轉錄變異體之鹼基序列。 The BAG1 line binds to BCL2, a membrane protein that inhibits the pathway that induces apoptosis or programmed cell death. The BAG1 line enhances the anti-apoptotic effect of BCL2, indicating a link between the proliferation factor receptor and the anti-apoptotic mechanism. BAG1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_004323.5, NM_001172415.1 (NP_004314.5, NP_001165886.1, AAH14774.2), etc.; number indicates NCBI database The registration number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the base sequence of the human BAG1 gene registered as a NM_004323.5 in the database is shown in SEQ ID NO: 57, and the amino acid sequence of the human BAG1 protein encoded by the human BAG1 gene is shown in SEQ ID NO:58. Further, in the present specification, BAG1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 58 encoded by the nucleotide sequence of SEQ ID NO: 57. Regarding BAG1, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 57 represents the base sequence of one of the transcribed variants.

BCL2L1屬於BCL2蛋白質家族，其形成異質或同型二聚物而與細胞質內之活性廣泛相關，成為控制抗細胞凋亡控制或細胞凋亡促進控制因子。BCL2L1存在於線粒體外膜，顯示出對線粒體外膜通道進行開放控制。BCL2L1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_138578.1,NM_001191.2,XM_011528966.1,XM_011528965.1,XM_011528961.1, XM_011528960.1,XM_011528964.1,XM_011528963.1,XM_011528962.1,XM_005260487.3,XM_005260486.2(NP_612815.1,NP_001182.1,AAH19307.1,XP_011527268.1,XP_011527267.1,XP_011527266.1,XP_011527265.1,XP_011527264.1,XP_011527263.1,XP_011527262.1,XP_005260544.1,XP_005260543.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_138578.1而登記於資料庫中之人類BCL2L1基因之鹼基序列示於序列編號59，將該人類BCL2L1基因所編碼之人類BCL2L1蛋白質之胺基酸序列示於序列編號60。再者，於本說明書中，BCL2L1並不限定於包含由序列編號59之鹼基序列所編碼之序列編號60之胺基酸序列的蛋白質。關於BCL2L1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號59之鹼基序列表示其中一個轉錄變異體之鹼基序列。 BCL2L1 belongs to the BCL2 protein family, which forms a heterogeneous or homodimer and is widely associated with activity in the cytoplasm, and is a controlling factor for controlling anti-apoptosis control or apoptosis. BCL2L1 is present in the mitochondrial outer membrane and shows open control of the mitochondrial outer membrane channel. BCL2L1 is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_138578.1, NM_001191.2, XM_011528966.1, XM_011528965.1, XM_011528961.1, XM_011528960.1, XM_011528964.1, XM_011528963.1, XM_011528962.1, XM_005260487.3, XM_005260486.2 (NP_612815.1, NP_001182.1, AAH19307.1, XP_011527268.1, XP_011527267.1, XP_011527266.1, XP_011527265. 1, XP_011527264.1, XP_011527263.1, XP_011527262.1, XP_005260544.1, XP_005260543.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human BCL2L1 gene registered in the database as NM_138578.1 is shown in SEQ ID NO: 59, and the amino acid sequence of the human BCL2L1 protein encoded by the human BCL2L1 gene is shown in SEQ ID NO: 60. Further, in the present specification, BCL2L1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 60 encoded by the nucleotide sequence of SEQ ID NO:59. Regarding BCL2L1, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 59 indicates the base sequence of one of the transcribed variants.

BFAR係二元功能細胞凋亡控制因子，其具有針對經由細胞死亡受體而誘發之細胞凋亡及經由線粒體因子而誘發之細胞凋亡之兩者的抗細胞凋亡活性。BFAR存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_016561.2,XM_006725196.2,XM_011546704.1,XM_005255350.2,XM_011522520.1(NP_057645.1,XP_011545006.1,XP_011520822.1,XP_006725259.1,XP_005255407.1,AAH03054.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_016561.2而登記於資料庫中之人類BFAR基因之鹼基序列示於序列編號61，將該人類BFAR基因所編碼之人類BFAR蛋白質之胺基酸序列示於序列編號62。再者，於本說明書中，BFAR並不限定於包含由序列編號61之鹼基序列所編碼之序列編號62之胺基酸序列的蛋白質。關於BFAR，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。 序列編號61之鹼基序列表示其中一個轉錄變異體之鹼基序列。 BFAR is a binary functional apoptosis control factor having anti-apoptotic activity against both apoptosis induced by cell death receptors and apoptosis induced by mitochondrial factors. BFAR is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_016561.2, XM_006725196.2, XM_011546704.1, XM_005255350.2, XM_011522520.1 (NP_057645.1, XP_011545006.1) , XP_011520822.1, XP_006725259.1, XP_005255407.1, AAH03054.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the base sequence of the human BFAR gene registered as a NM_016561.2 in the database is shown in SEQ ID NO: 61, and the amino acid sequence of the human BFAR protein encoded by the human BFAR gene is shown in SEQ ID NO:62. Further, in the present specification, BFAR is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 62 encoded by the nucleotide sequence of SEQ ID NO: 61. Regarding BFAR, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 61 indicates the base sequence of one of the transcribed variants.

已知CFLAR係細胞凋亡之控制因子，其結構與半胱天冬酶8類似。但是，CFLAR不具有半胱天冬酶活性，會被半胱天冬酶8分解為2個肽。CFLAR存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_003879.5,NM_001202519.1,NM_001202518.1,NM_001308043.1,NM_001308042.1,NM_001202517.1,NM_001202516.1,NM_001127184.2,NM_001202515.1,NM_001127183.2,XM_011512100.1(NP_003870.4,NP_001294972.1,NP_001294971.1,NP_001189448.1,NP_001189446.1,NP_001189445.1,NP_001189444.1,NP_001120656.1,XP_011510402.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_003879.5而登記於資料庫中之人類CFLAR基因之鹼基序列示於序列編號63，將該人類CFLAR基因所編碼之人類CFLAR蛋白質之胺基酸序列示於序列編號64。再者，於本說明書中，CFLAR並不限定於包含由序列編號63之鹼基序列所編碼之序列編號64之胺基酸序列的蛋白質。關於CFLAR，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號63之鹼基序列表示其中一個轉錄變異體之鹼基序列。 A control factor for apoptosis of CFLAR cells is known, and its structure is similar to that of caspase 8. However, CFLAR does not have caspase activity and is broken down into two peptides by caspase 8. CFLAR is present in a variety of animals, including humans, and its sequence information is also known (eg, human: NM_003879.5, NM_001202519.1, NM_001202518.1, NM_001308043.1, NM_001308042.1, NM_001202517.1, NM_001202516.1 , NM_001127184.2, NM_001202515.1, NM_001127183.2, XM_011512100.1 (NP_003870.4, NP_001294972.1, NP_001294971.1, NP_001189448.1, NP_001189446.1, NP_001189445.1, NP_001189444.1, NP_001120656.1, XP_011510402 .1) Etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human CFLAR gene registered as a NM_003879.5 in the database is shown in SEQ ID NO: 63, and the amino acid sequence of the human CFLAR protein encoded by the human CFLAR gene is shown in SEQ ID NO: 64. Further, in the present specification, CFLAR is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 64 encoded by the nucleotide sequence of SEQ ID NO: 63. Regarding CFLAR, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 63 indicates the base sequence of one of the transcribed variants.

IL2係作為對於T及B淋巴球之增殖而言重要之分泌細胞激素的介白素2。IL2存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000586.3(NP_000577.2)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000586.3而登記於資料庫中之人類IL2基因之鹼基序列示於序列編號65，將該人類IL2基因所編碼之人類IL2蛋白質之胺基酸序列示於序列編號66。再者，於本說明書中，IL2並不限定 於包含由序列編號65之鹼基序列所編碼之序列編號66之胺基酸序列的蛋白質。關於IL2，有存在複數個轉錄變異體之可能性。序列編號65之鹼基序列表示一個轉錄變異體之鹼基序列。 IL2 is a secreting cytokine interleukin 2 that is important for the proliferation of T and B lymphocytes. IL2 is present in various animals including humans, and its sequence information is also known (for example, human: NM_000586.3 (NP_000577.2), etc.; the number indicates the registration number of the NCBI database, and the base sequence is outside the parentheses, in parentheses. Is the number of the amino acid sequence). As an example, the nucleotide sequence of the human IL2 gene registered as a NM_000586.3 in the database is shown in SEQ ID NO: 65, and the amino acid sequence of the human IL2 protein encoded by the human IL2 gene is shown in SEQ ID NO: 66. Furthermore, in this specification, IL2 is not limited A protein comprising the amino acid sequence of SEQ ID NO: 66 encoded by the nucleotide sequence of SEQ ID NO: 65. Regarding IL2, there is a possibility that there are a plurality of transcriptional variants. The nucleotide sequence of SEQ ID NO: 65 represents the base sequence of a transcribed variant.

MALT1係由於黏膜關聯淋巴組織淋巴瘤中於桿狀病毒IAP重複蛋白質3(細胞凋亡抑制因子2)與免疫球蛋白重鏈座間之染色體易位再構成之基因所編碼。認為MALT1係將NFκB活化。MALT1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_173844.2、NM_006785.3、XM_011525794.1(NP_776216.1、NP_006776.1、XP_011524096.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_006785.3而登記於資料庫中之人類MALT1基因之鹼基序列示於序列編號67，將該人類MALT1基因所編碼之人類MALT1蛋白質之胺基酸序列示於序列編號68。再者，於本說明書中，MALT1並不限定於包含由序列編號67之鹼基序列所編碼之序列編號68之胺基酸序列的蛋白質。關於MALT1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號67之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MALT1 is encoded by a gene that reconstitutes a chromosomal translocation between baculovirus IAP repeat protein 3 (apoptosis inhibitor 2) and an immunoglobulin heavy chain locus in mucosal-associated lymphoid tissue lymphoma. MALT1 is thought to activate NFκB. MALT1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_173844.2, NM_006785.3, XM_011525794.1 (NP_776216.1, NP_006776.1, XP_011524096.1), etc.; Indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the base sequence of the human MALT1 gene registered as a NM_006785.3 in the database is shown in SEQ ID NO: 67, and the amino acid sequence of the human MALT1 protein encoded by the human MALT1 gene is shown in SEQ ID NO: 68. Further, in the present specification, MALT1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 68 encoded by the nucleotide sequence of SEQ ID NO: 67. Regarding MALT1, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 67 indicates the base sequence of one of the transcribed variants.

MCL1係作為Bcl-2家族成員之抗細胞凋亡蛋白質。關於MCL1基因，藉由選擇性剪切所產生之變異體中之最長者會抑制細胞凋亡，而提高細胞之存活，更短之變異體會誘發細胞凋亡而誘導細胞死亡。MCL1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_021960.4、NM_001197320.1、NM_182763.2(NP_068779.1、NP_001184249.1、NP_877495.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_021960.4而登記於資料庫中之人類MCL1基因之鹼基序列示於序列編號69，將該人類MCL1基因 所編碼之人類MCL1蛋白質之胺基酸序列示於序列編號70。再者，於本說明書中，MCL1並不限定於包含由序列編號69之鹼基序列所編碼之序列編號70之胺基酸序列的蛋白質。關於MCL1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號69之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MCL1 is an anti-apoptotic protein that is a member of the Bcl-2 family. Regarding the MCL1 gene, the longest of the variants produced by selective splicing inhibits apoptosis and increases cell survival, and shorter variants induce apoptosis and induce cell death. MCL1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_021960.4, NM_001197320.1, NM_182763.2 (NP_068779.1, NP_001184249.1, NP_877495.1), etc.; Indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the base sequence of the human MCL1 gene registered as a NM_021960.4 in the database is shown in SEQ ID NO: 69, and the human MCL1 gene is shown. The amino acid sequence of the encoded human MCL1 protein is shown in SEQ ID NO:70. Further, in the present specification, MCL1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 70 encoded by the nucleotide sequence of SEQ ID NO: 69. Regarding MCL1, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 69 indicates the base sequence of one of the transcribed variants.

已知MKL1係與作為對於平滑肌細胞分化有用之控制因子的轉錄因子心肌素(myocardin)相互作用。MKL1大部分存在於細胞核，幫助訊號自細胞骨架向細胞核進行傳遞。MKL1基因與和RNA結合結構蛋白質15基因融合之易位相關。MKL1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001282662.1、NM_001282660.1、NM_020831.4、NM_001282661.1、XM_011530287.1、XM_011530286.1、XM_011530285.1、XM_011530284.1、XM_011530283.1、XM_005261691.3(NP_001269591.1、NP_001269589.1、NP_065882.1、NP_001269590.1、XP_011528589.1、XP_011528588.1、XP_011528587.1、XP_011528586.1、XP_011528585.1、XP_005261751.1、XP_005261749.1、XP_005261748.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001282662.1而登記於資料庫中之人類MKL1基因之鹼基序列示於序列編號71，將該人類MKL1基因所編碼之人類MKL1蛋白質之胺基酸序列示於序列編號72。再者，於本說明書中，MKL1並不限定於包含由序列編號71之鹼基序列所編碼之序列編號72之胺基酸序列的蛋白質。關於MKL1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號71之鹼基序列表示其中一個轉錄變異體之鹼基序列。 The MKL1 line is known to interact with the transcription factor myocardin, a control factor useful for smooth muscle cell differentiation. MKL1 is mostly present in the nucleus, helping to transmit signals from the cytoskeleton to the nucleus. The MKL1 gene is associated with a translocation of the RNA-binding structural protein 15 gene. MKL1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_001282662.1, NM_001282660.1, NM_020831.4, NM_001282661.1, XM_011530287.1, XM_011530286.1, XM_011530285.1 , XM_011530284.1, XM_011530283.1, XM_005261691.3 (NP_001269591.1, NP_001269589.1, NP_065882.1, NP_001269590.1, XP_011528589.1, XP_011528588.1, XP_011528587.1, XP_011528586.1, XP_011528585.1, XP_005261751 .1, XP_005261749.1, XP_005261748.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human MKL1 gene registered in the database as NM_001282662.1 is shown in SEQ ID NO: 71, and the amino acid sequence of the human MKL1 protein encoded by the human MKL1 gene is shown in SEQ ID NO:72. Further, in the present specification, MKL1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 72 encoded by the nucleotide sequence of SEQ ID NO:71. Regarding MKL1, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 71 indicates the base sequence of one of the transcribed variants.

MPO係作為於骨髓分化期間所合成之血紅素蛋白質的骨髓過氧化酶，構成嗜中性球藍色顆粒之主成分。MPO係生成對於嗜中性球之殺菌活性發揮中心作用之次鹵酸。MPO存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_000250.1、XM_011524823.1、XM_011524822.1、XM_011524821.1(NP_000241.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_000250.1而登記於資料庫中之人類MPO基因之鹼基序列示於序列編號73，將該人類MPO基因所編碼之人類MPO蛋白質之胺基酸序列示於序列編號74。再者，於本說明書中，MPO並不限定於包含由序列編號73之鹼基序列所編碼之序列編號74之胺基酸序列的蛋白質。關於MPO，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號73之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MPO is a main component of neutrophil blue particles as a bone marrow peroxidase of heme protein synthesized during bone marrow differentiation. The MPO system produces a hypohalous acid that plays a central role in the bactericidal activity of the neutrophil. MPO exists in various animals including humans, and its sequence information is also known (for example, human: NM_000250.1, XM_011524823.1, XM_011524822.1, XM_011524821.1 (NP_000241.1), etc.; number indicates NCBI database The registration number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the base sequence of the human MPO gene registered as a NM_000250.1 in the database is shown in SEQ ID NO: 73, and the amino acid sequence of the human MPO protein encoded by the human MPO gene is shown in SEQ ID NO: 74. Further, in the present specification, MPO is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 74 encoded by the nucleotide sequence of SEQ ID NO: 73. Regarding the MPO, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 73 indicates the base sequence of one of the transcribed variants.

MTL5係金屬硫蛋白狀蛋白質，顯示出於小鼠之睾丸及卵巢中特異性地進行表現。再者，認為金屬硫蛋白於細胞增殖及分化之控制方面具有中心作用，與精子形成相關。MTL5存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_004923.3、NM_001039656.1、XM_011545404.1、XM_011545403.1、XM_011545402.1(NP_001034745.1、NP_004914.2、XP_011543706.1、XP_011543705.1、XP_011543704.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_004923.3而登記於資料庫中之人類MTL5基因之鹼基序列示於序列編號75，將該人類MTL5基因所編碼之人類MTL5蛋白質之胺基酸序列示於序列編號76。再者，於本說明書中，MTL5並不限定於包含由序列編號75之鹼基序列所編碼之序列編號76之胺基酸序列的蛋白質。關於MTL5，如上所述以複數個寄存編 號登記序列資訊，存在複數個轉錄變異體。序列編號75之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MTL5 is a metallothionein-like protein which is shown to be specifically expressed in the testes and ovaries of mice. Furthermore, metallothionein is believed to play a central role in the control of cell proliferation and differentiation and is involved in spermatogenesis. MTL5 is present in various animals including humans, and its sequence information is also known (for example, human: NM_004923.3, NM_001039656.1, XM_011545404.1, XM_011545403.1, XM_011545402.1 (NP_001034745.1, NP_004914.2) , XP_011543706.1, XP_011543705.1, XP_011543704.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human MTL5 gene which is registered in the database as NM_004923.3 is shown in SEQ ID NO: 75, and the amino acid sequence of the human MTL5 protein encoded by the human MTL5 gene is shown in SEQ ID NO: 76. Further, in the present specification, MTL5 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 76 encoded by the nucleotide sequence of SEQ ID NO: 75. Regarding MTL5, as described above, a plurality of registrations Number registration sequence information, there are multiple transcription variants. The nucleotide sequence of SEQ ID NO: 75 indicates the base sequence of one of the transcribed variants.

MYBL2係作為轉錄因子之屬於MYB家族之核蛋白質，與細胞週期之進行相關。MYBL2於S期被週期蛋白A/週期蛋白依賴性激酶2所磷酸化，具有活化因子及抑制因子之兩活性。MYBL2存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001278610.1、NM_002466.3(NP_001265539.1、NP_002457.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_002466.3而登記於資料庫中之人類MYBL2基因之鹼基序列示於序列編號77，將該人類MYBL2基因所編碼之人類MYBL2蛋白質之胺基酸序列示於序列編號78。再者，於本說明書中，MYBL2並不限定於包含由序列編號77之鹼基序列所編碼之序列編號78之胺基酸序列的蛋白質。關於MYBL2，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號77之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MYBL2 is a nuclear protein belonging to the MYB family as a transcription factor and is involved in the cell cycle. MYBL2 is phosphorylated by cyclin A/cyclin-dependent kinase 2 in the S phase, and has two activities of an activating factor and an inhibitory factor. MYBL2 is present in various animals including humans, and its sequence information is also known (for example, human: NM_001278610.1, NM_002466.3 (NP_001265539.1, NP_002457.1), etc.; the number indicates the registration number of the NCBI database, The base sequence is outside the parentheses, and the amino acid sequence number is in parentheses. As an example, the nucleotide sequence of the human MYBL2 gene registered in the database as NM_002466.3 is shown in SEQ ID NO: 77, and the amino acid sequence of the human MYBL2 protein encoded by the human MYBL2 gene is shown in SEQ ID NO: 78. Further, in the present specification, MYBL2 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 78 encoded by the nucleotide sequence of SEQ ID NO: 77. Regarding MYBL2, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 77 indicates the base sequence of one of the transcribed variants.

已知MYO18A係肌球蛋白18A，其與8p11骨髓增殖性症候群相關。MYO18A具有運動活性及ATPase活性。MYO18A存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_203318.1、NM_078471.3(NP_976063.1、NP_510880.2)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_078471.3而登記於資料庫中之人類MYO18A基因之鹼基序列示於序列編號79，將該人類MYO18A基因所編碼之人類MYO18A蛋白質之胺基酸序列示於序列編號80。再者，於本說明書中，MYO18A並不限定於包含由序列編號79之鹼基序列所編碼之序列編號80之胺基酸序列的蛋白質。關於MYO18A，如上 所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號79之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MYO18A myosin 18A, which is associated with 8p11 myeloproliferative syndrome, is known. MYO18A has motor activity and ATPase activity. MYO18A is present in various animals including humans, and its sequence information is also known (for example, human: NM_203318.1, NM_078471.3 (NP_976063.1, NP_510880.2), etc.; the number indicates the registration number of the NCBI database, The base sequence is outside the parentheses, and the amino acid sequence number is in parentheses. As an example, the nucleotide sequence of the human MYO18A gene registered as a NM_078471.3 in the database is shown in SEQ ID NO: 79, and the amino acid sequence of the human MYO18A protein encoded by the human MYO18A gene is shown in SEQ ID NO: 80. Further, in the present specification, MYO18A is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 80 encoded by the nucleotide sequence of SEQ ID NO:79. About MYO18A, as above The sequence information is registered in a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 79 indicates the base sequence of one of the transcribed variants.

另一方面，PI3K訊號傳遞路徑相關蛋白質係與PI3K/AKT訊號傳遞路徑之蛋白質中除Akt1以外之蛋白質相關，換言之，係除Akt1以外之PI3K/AKT訊號傳遞路徑相關蛋白質。再者，關於PI3K/AKT訊號傳遞路徑，例如揭示於Cell 2007 Jun 29；129(7)：1261-74。 On the other hand, the PI3K signaling pathway-related protein is associated with proteins other than Aktl in proteins of the PI3K/AKT signaling pathway, in other words, PI3K/AKT signaling pathway-related proteins other than Akt1. Furthermore, regarding the PI3K/AKT signal transmission path, for example, it is disclosed in Cell 2007 Jun 29; 129(7): 1261-74.

具體而言，作為若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質，可列舉選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。該等14種PI3K訊號傳遞路徑相關蛋白質中，可將1種PI3K訊號傳遞路徑相關蛋白質與GST-π一併加以抑制，亦可將2種以上PI3K訊號傳遞路徑相關蛋白質與GST-π一併加以抑制。 Specifically, the PI3K signal transmission path-related protein which exhibits synthetic lethality when combined with GST-π is selected from MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, At least one of the PI3K signaling pathway-associated proteins of the group consisting of EIF4E, ILK, MTCP1, PIK3CA, and SRF. Among the 14 kinds of PI3K signal transmission pathway-related proteins, one PI3K signal transmission pathway-related protein can be inhibited together with GST-π, and two or more PI3K signal-path-related proteins can be combined with GST-π. inhibition.

尤其是，作為PI3K訊號傳遞路徑相關蛋白質，較佳為將選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG及RAC1所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質與GST-π一併加以抑制。該等7種PI3K訊號傳遞路徑相關蛋白質係與分別單獨進行抑制之情形或單獨抑制GST-π之情形相比，顯示出顯著高之細胞增殖抑制效果者。因此，作為若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質，較佳為選自該等7種PI3K訊號傳遞路徑相關蛋白質之中。 In particular, as the PI3K signal-path-related protein, at least one PI3K signal-path-related protein selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, and RAC1 is preferably combined with GST-π. Suppress it. These seven kinds of PI3K signal transmission pathway-related protein lines showed significantly higher cell proliferation inhibitory effects than those in which inhibition was performed alone or in the case of inhibiting GST-π alone. Therefore, as a PI3K signal transmission path-related protein which exhibits a synthetic lethality when it is suppressed together with GST-π, it is preferably selected from the seven kinds of PI3K signal-path-related proteins.

MTOR(mechanistic target of rapamycin，雷帕黴素之標靶蛋白質)係雷帕黴素之標靶蛋白質，已知為絲胺酸-蘇胺酸激酶之一種。MTOR屬於磷脂醯肌醇激酶相關激酶，顯示出以對DNA損傷及營養枯竭之應力的細胞反應為媒介。已知MTOR係作為因細胞週期停止及FKBP12-雷帕黴素複合體引起之免疫抑制效果之靶而發揮作用。MTOR存在於 包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_004958.3,XM_005263438.1,XM_011541166.1(NP_004949.1,XP_005263495.1,XP_005263495.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_004958.3而登記於資料庫中之人類MTOR基因之鹼基序列示於序列編號81，將該人類MTOR基因所編碼之人類MTOR蛋白質之胺基酸序列示於序列編號82。再者，於本說明書中，MTOR並不限定於包含由序列編號81之鹼基序列所編碼之序列編號82之胺基酸序列的蛋白質。關於MTOR，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號81之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MTOR (mechanistic target of rapamycin, the target protein of rapamycin) is a target protein of rapamycin, which is known as a kind of serine-threonine kinase. MTOR belongs to the phospholipid spectinokinase-associated kinase and has been shown to mediate cellular responses to stresses on DNA damage and nutrient depletion. MTOR is known to function as a target for the immunosuppressive effect caused by cell cycle arrest and FKBP12-rapamycin complex. MTOR exists in The sequence information is also known in various animals including humans (for example, human: NM_004958.3, XM_005263438.1, XM_011541166.1 (NP_004949.1, XP_005263495.1, XP_005263495.1), etc.; number indicates NCBI data The registration number of the library, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the base sequence of the human MTOR gene registered as a NM_004958.3 in the database is shown in SEQ ID NO: 81, and the amino acid sequence of the human MTOR protein encoded by the human MTOR gene is shown in SEQ ID NO: 82. Further, in the present specification, MTOR is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 82 encoded by the nucleotide sequence of SEQ ID NO: 81. Regarding MTOR, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 81 represents the base sequence of one of the transcribed variants.

IRAK1(interleukin 1 receptor associated kinase 1，介白素1受體相關激酶1)係介白素1受體相關激酶1，其係因刺激而作用於介白素1受體之絲胺酸-蘇胺酸激酶之一。IRAK1成為與轉錄因子NFκB相關之IL1誘導性上調之部分原因。IRAK1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001025243.1,NM_001025242.1,NM_001569.3,XM_011531158.1,XM_005274668.2(NP_001020414.1,NP_001020413.1,NP_001560.2,XP_011529460.1,XP_005274725.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001025243.1而登記於資料庫中之人類IRAK1基因之鹼基序列示於序列編號83，將該人類IRAK1基因所編碼之人類IRAK1蛋白質之胺基酸序列示於序列編號84。再者，於本說明書中，IRAK1並不限定於包含由序列編號83之鹼基序列所編碼之序列編號84之胺基酸序列的蛋白質。關於IRAK1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號83之鹼基序列表示其中一個 轉錄變異體之鹼基序列。 IRAK1 (interleukin 1 receptor associated kinase 1, interleukin-1 receptor-associated kinase 1) is a receptor for interleukin-1 receptor-associated kinase 1 which acts on the interleukin-1 receptor-dependent serine-threonine One of the acid kinases. IRAK1 is part of the reason for the upregulation of IL1 associated with the transcription factor NFκB. IRAK1 is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_001025243.1, NM_001025242.1, NM_001569.3, XM_011531158.1, XM_005274668.2 (NP_001020414.1, NP_001020413.1) , NP_001560.2, XP_011529460.1, XP_005274725.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human IRAK1 gene registered in the database as NM_001025243.1 is shown in SEQ ID NO: 83, and the amino acid sequence of the human IRAK1 protein encoded by the human IRAK1 gene is shown in SEQ ID NO: 84. Further, in the present specification, IRAK1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 84 encoded by the nucleotide sequence of SEQ ID NO: 83. Regarding IRAK1, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The base sequence of SEQ ID NO: 83 represents one of them. The base sequence of the transcriptional variant.

IRS1(insulin receptor substrate 1，胰島素受體受質1)已知為會被胰島素受體酪胺酸激酶所磷酸化之蛋白質。IRS1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_005544.2(NP_005535.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_005544.2而登記於資料庫中之人類IRS1基因之鹼基序列示於序列編號85，將該人類IRS1基因所編碼之人類IRS1蛋白質之胺基酸序列示於序列編號86。再者，於本說明書中，IRS1並不限定於包含由序列編號85之鹼基序列所編碼之序列編號86之胺基酸序列的蛋白質。關於IRS1，有存在複數個轉錄變異體之可能性。序列編號85之鹼基序列表示其中一個轉錄變異體之鹼基序列。 IRS1 (insulin receptor substrate 1, insulin receptor substrate 1) is known as a protein that is phosphorylated by the insulin receptor tyrosine kinase. IRS1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_005544.2 (NP_005535.1), etc.; the number indicates the registration number of the NCBI database, and the base sequence is outside the parentheses, in parentheses. Is the number of the amino acid sequence). As an example, the nucleotide sequence of the human IRS1 gene registered in the database as NM_005544.2 is shown in SEQ ID NO: 85, and the amino acid sequence of the human IRS1 protein encoded by the human IRS1 gene is shown in SEQ ID NO: 86. Further, in the present specification, IRS1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 86 encoded by the nucleotide sequence of SEQ ID NO:85. Regarding IRS1, there is a possibility that there are a plurality of transcriptional variants. The nucleotide sequence of SEQ ID NO: 85 represents the base sequence of one of the transcribed variants.

MYD88(myeloid differentiation primary response 88，骨髓分化原初反應蛋白88)係實現先天性及適應性免疫應答之主要功能之細胞質附加蛋白質。MYD88係作為介白素1及Toll狀受體訊號路徑中必須之訊號傳遞物質而發揮功能。該等訊號路徑控制較多之炎症性基因之活化。MYD88具有N末端之死區域及C末端之Toll-介白素1受體區域。MYD88存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001172567.1,NM_002468.4,NM_001172569.1,NM_001172568.1,NM_001172566.1,XM_005265172.1,XM_006713170.1(NP_001166038.1,NP_002459.2,NP_001166040.1,NP_001166039.1,NP_001166037.1,XP_005265229.1,XP_006713233.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001172567.1而登記於資料庫中之人MYD88基因之鹼基序列示於序列編號87，該人MYD88基因所編碼之人MYD88蛋白質之胺基酸序列示於序列編號88。再 者，於本說明書中，MYD88並不限定於包含由序列編號87之鹼基序列所編碼之序列編號88之胺基酸序列的蛋白質。關於MYD88，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號87之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MYD88 (myeloid differentiation primary response 88) is a cytoplasmic additional protein that fulfills the primary function of the innate and adaptive immune response. MYD88 functions as a signal-transferring substance necessary for the interleukin-1 and Toll-like receptor signal paths. These signal paths control the activation of more inflammatory genes. MYD88 has a N-terminal dead region and a C-terminal Toll-Interleukin 1 receptor region. MYD88 is present in various animals including humans, and its sequence information is also known (for example, human: NM_001172567.1, NM_002468.4, NM_001172569.1, NM_001172568.1, NM_001172566.1, XM_005265172.1, XM_006713170.1 (NP_001166038.1, NP_002459.2, NP_001166040.1, NP_001166039.1, NP_001166037.1, XP_005265229.1, XP_006713233.1), etc.; the number indicates the registration number of the NCBI database, the base sequence is outside the parentheses, and the amine is in parentheses. The number of the base acid sequence). As an example, the nucleotide sequence of the human MYD88 gene registered as a NM_001172567.1 in the database is shown in SEQ ID NO: 87, and the amino acid sequence of the human MYD88 protein encoded by the human MYD88 gene is shown in SEQ ID NO: 88. again In the present specification, MYD88 is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 88 encoded by the nucleotide sequence of SEQ ID NO: 87. Regarding MYD88, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 87 indicates the base sequence of one of the transcribed variants.

NFKB1(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1，B細胞1中之κ輕鏈多肽基因增強子之核因子)係105kD之蛋白質，於藉由26S蛋白酶體轉譯時接受加工成為50kD之蛋白質。該105kD之蛋白質係Rel蛋白質特異性轉錄抑制劑，該50kD之蛋白質係NFκ-B蛋白質(NFKB)複合體中之DNA結合次單元。NFKB1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_003998.3,NM_001165412.1,XM_011532006.1,XM_011532007.1,XM_011532008.1,XM_011532009.1(NP_003989.2,NP_001158884.1,XP_011530308.1,XP_011530309.1,XP_011530310.1,XP_011530311.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_003998.3而登記於資料庫中之人類NFKB1基因之鹼基序列示於序列編號89，將該人類NFKB1基因所編碼之人類NFKB1蛋白質之胺基酸序列示於序列編號90。再者，於本說明書中，NFKB1並不限定於包含由序列編號89之鹼基序列所編碼之序列編號90之胺基酸序列的蛋白質。關於NFKB1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號89之鹼基序列表示其中一個轉錄變異體之鹼基序列。 NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1, a nuclear factor of κ light chain polypeptide gene enhancer in B cell 1) is a 105 kD protein that is processed into 50 kD when translated by the 26S proteasome. protein. The 105 kD protein is a Rel protein-specific transcriptional inhibitor, and the 50 kD protein is a DNA-binding subunit in the NFκB protein (NFKB) complex. NFKB1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_003998.3, NM_001165412.1, XM_011532006.1, XM_011532007.1, XM_011532008.1, XM_011532009.1 (NP_003989.2) , NP_001158884.1, XP_011530308.1, XP_011530309.1, XP_011530310.1, XP_011530311.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human NFKB1 gene which is registered in the database as NM_003998.3 is shown in SEQ ID NO: 89, and the amino acid sequence of the human NFKB1 protein encoded by the human NFKB1 gene is shown in SEQ ID NO: 90. Further, in the present specification, NFKB1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 90 encoded by the nucleotide sequence of SEQ ID NO: 89. Regarding NFKB1, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 89 indicates the base sequence of one of the transcribed variants.

已知PIK3CG(phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit gamma，4,5-二磷酸磷脂醯肌醇3-激酶觸媒次單元γ)與其他1型觸媒次單元(p110-α、p110-β及p110-δ)同樣地，與p85控制次單元結合而形成PI3K。PIK3CG存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001282426.1, NM_001282427.1,NM_002649.3,XM_011516316.1,XM_011516317.1,XM_005250443.2(NP_001269355.1,NP_001269356.1,NP_002640.2,XP_011514618.1,XP_011514619.1,XP_005250500.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001282426.1而登記於資料庫中之人類PIK3CG基因之鹼基序列示於序列編號91，將該人類PIK3CG基因所編碼之人類PIK3CG蛋白質之胺基酸序列示於序列編號92。再者，於本說明書中，PIK3CG並不限定於包含由序列編號91之鹼基序列所編碼之序列編號92之胺基酸序列的蛋白質。關於PIK3CG，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號91之鹼基序列表示其中一個轉錄變異體之鹼基序列。 It is known that PIK3CG (phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit gamma, 4,5-diphospholipid phosphoinositide 3-kinase catalytic subunit γ) and other type 1 catalytic subunits (p110-α) Similarly, p110-β and p110-δ) combine with the p85 control subunit to form PI3K. PIK3CG is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_001282426.1, NM_001282427.1, NM_002649.3, XM_011516316.1, XM_011516317.1, XM_005250443.2 (NP_001269355.1, NP_001269356.1, NP_002640.2, XP_011514618.1, XP_011514619.1, XP_005250500.1), etc.; The registration number of the library, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human PIK3CG gene registered as a NM_001282426.1 in the database is shown in SEQ ID NO: 91, and the amino acid sequence of the human PIK3CG protein encoded by the human PIK3CG gene is shown in SEQ ID NO:92. Further, in the present specification, PIK3CG is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 92 encoded by the nucleotide sequence of SEQ ID NO: 91. Regarding PIK3CG, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 91 indicates the base sequence of one of the transcribed variants.

已知RAC1(ras-related C3 botulinum toxin substrate 1，ras相關C3肉毒桿菌毒素受質1(rho family,small GTP binding protein Rac1，rho家族之小GTP結合蛋白質Rac1))係小GTP結合性蛋白質中之屬於RAS超家族之GTPase。該屬於超家族之因子係控制包括成長、細胞骨架再構建及蛋白激酶之活化在內之多種多樣之細胞內事件。RAC1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_018890.3,NM_006908.4(NP_061485.1,NP_008839.2)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_018890.3而登記於資料庫中之人類RAC1基因之鹼基序列示於序列編號93，將該人類RAC1基因所編碼之人類RAC1蛋白質之胺基酸序列示於序列編號94。再者，於本說明書中，RAC1並不限定於包含由序列編號93之鹼基序列所編碼之序列編號94之胺基酸序列的蛋白質。關於RAC1，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號93之鹼基序列表示其中一個轉錄變異體之鹼基序列。 RAC1 (ras-related C3 botulinum toxin substrate 1, ras-related C3 botulinum toxin 1 (rho family, small GTP binding protein Rac1), small GTP-binding protein Rac1) is known to be a small GTP-binding protein. It belongs to the GTPase of the RAS superfamily. This superfamily factor controls a wide variety of intracellular events including growth, cytoskeletal remodeling, and activation of protein kinases. RAC1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_018890.3, NM_006908.4 (NP_061485.1, NP_008839.2), etc.; the number indicates the registration number of the NCBI database, The base sequence is outside the parentheses, and the amino acid sequence number is in parentheses. As an example, the nucleotide sequence of the human RAC1 gene registered in the database as NM_018890.3 is shown in SEQ ID NO: 93, and the amino acid sequence of the human RAC1 protein encoded by the human RAC1 gene is shown in SEQ ID NO: 94. Further, in the present specification, RAC1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 94 encoded by the nucleotide sequence of SEQ ID NO:93. Regarding RAC1, as described above, the sequence information is registered with a plurality of registration numbers, and there are a plurality of transcription variants. The nucleotide sequence of SEQ ID NO: 93 indicates the base sequence of one of the transcribed variants.

AKT3(v-akt murine thymoma viral oncogene homolog 3，v-akt小鼠胸腺瘤病毒致癌基因同系物3)已知為亦稱為PKB之絲胺酸-蘇胺酸蛋白激酶家族之AKT之成員。已知AKT激酶係應答胰島素及成長因子之細胞訊號系統中之控制因子。該等不限於肝糖合成及葡萄糖取入，亦與細胞增殖、分化、細胞凋亡及腫瘤形成之各種生物學過程相關。顯示出該激酶因源自血小板之成長因子(PDGF)、胰島素及胰島素狀成長因子1(IGF1)而受到刺激。AKT3存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_181690.2,NM_001206729.1,NM_005465.4,XM_005272995.2,XM_011544011.1,XM_005272994.3,XM_005272997.3,XM_011544014.1,XM_011544012.1,XM_011544013.1,XM_006711726.2(NP_859029.1,NP_001193658.1,NP_005456.1,XP_005273052.1,XP_011542313.1,XP_005273051.1,XP_005273054.1,XP_011542316.1,XP_011542314.1,XP_011542315.1,XP_006711789.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_181690.2而登記於資料庫中之人類AKT3基因之鹼基序列示於序列編號95，將該人類AKT3基因所編碼之人類AKT3蛋白質之胺基酸序列示於序列編號96。再者，於本說明書中，AKT3並不限定於包含由序列編號95之鹼基序列所編碼之序列編號96之胺基酸序列的蛋白質。關於AKT3，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號95之鹼基序列表示其中一個轉錄變異體之鹼基序列。 AKT3 (v-akt murine thymoma viral oncogene homolog 3, v-akt mouse thymoma virus oncogene homolog 3) is known as a member of the AKT of the family of serine-threonine protein kinases also known as PKB. The AKT kinase is known to be a control factor in the cellular signaling system of insulin and growth factors. These are not limited to glycogen synthesis and glucose ingestion, but are also associated with various biological processes of cell proliferation, differentiation, apoptosis, and tumor formation. This kinase was shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). AKT3 is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_181690.2, NM_001206729.1, NM_005465.4, XM_005272995.2, XM_011544011.1, XM_005272994.3, XM_005272997.3 , XM_011544014.1, XM_011544012.1, XM_011544013.1, XM_006711726.2 (NP_859029.1, NP_001193658.1, NP_005456.1, XP_005273052.1, XP_011542313.1, XP_005273051.1, XP_005273054.1, XP_011542316.1, XP_011542314 .1, XP_011542315.1, XP_006711789.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human AKT3 gene which is registered in the database as NM_181690.2 is shown in SEQ ID NO: 95, and the amino acid sequence of the human AKT3 protein encoded by the human AKT3 gene is shown in SEQ ID NO: 96. Further, in the present specification, AKT3 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 96 encoded by the nucleotide sequence of SEQ ID NO: 95. Regarding AKT3, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 95 indicates the base sequence of one of the transcribed variants.

已知EIF4B(eukaryotic translation initiation factor 4B，真核轉譯起始因子4B)係與由PI3K-Akt訊號路徑及GPCR產生之訊號相關之蛋白質。已知EIF4B係mRNA與核糖體結合所必需，具有與EIF4-F及EIF4-A密接相關之功能，於EIF4-F及ATP之存在下與mRNA之5'末端帽近端 結合，促進ATPase之活性，促進EIF4-A及EIF4-F之ATP依賴型RNA解鏈活性。EIF4B存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001300821.1,NM_001417.5,XM_006719274.1(NP_001287750.1,NP_001408.2,XP_006719337.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001300821.1而登記於資料庫中之人類EIF4B基因之鹼基序列示於序列編號97，將該人類EIF4B基因所編碼之人類EIF4B蛋白質之胺基酸序列示於序列編號98。再者，於本說明書中，EIF4B並不限定於包含由序列編號97之鹼基序列所編碼之序列編號98之胺基酸序列的蛋白質。關於EIF4B，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號97之鹼基序列表示其中一個轉錄變異體之鹼基序列。 EIF4B (eukaryotic translation initiation factor 4B) is known to be a protein associated with signals generated by the PI3K-Akt signal pathway and GPCR. It is known that EIF4B mRNA is required for binding to ribosomes, and has the function of binding to EIF4-F and EIF4-A. It is proximal to the 5' end cap of mRNA in the presence of EIF4-F and ATP. Binding promotes the activity of ATPase and promotes the ATP-dependent RNA melting activity of EIF4-A and EIF4-F. EIF4B is present in various animals including humans, and its sequence information is also known (for example, human: NM_001300821.1, NM_001417.5, XM_006719274.1 (NP_001287750.1, NP_001408.2, XP_006719337.1), etc.; Indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human EIF4B gene which is registered in the database as NM_001300821.1 is shown in SEQ ID NO: 97, and the amino acid sequence of the human EIF4B protein encoded by the human EIF4B gene is shown in SEQ ID NO: 98. Further, in the present specification, EIF4B is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 98 encoded by the nucleotide sequence of SEQ ID NO:97. Regarding EIF4B, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 97 indicates the base sequence of one of the transcribed variants.

已知EIF4E(eukaryotic translation initiation factor 4E，真核轉譯起始因子4E)為構成識別mRNA之5'末端之7-甲基鳥苷帽結構的真核生物轉譯開始因子4F複合體的蛋白質。EIF4E藉由將核糖體集中為5'末端帽結構而對開始轉譯進行輔助。EIF4E之與4F複合體之結合成為轉譯開始之限速階段。EIF4E存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001968.3,NM_001130679.1,NM_001130678.1,XM_006714126.2,XM_006714127.2(NP_001959.1,NP_001124151.1,NP_001124150.1,XP_006714189.1,XP_006714190.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001968.3而登記於資料庫中之人類EIF4E基因之鹼基序列示於序列編號99，將該人類EIF4E基因所編碼之人類EIF4E蛋白質之胺基酸序列示於序列編號100。再者，於本說明書中，EIF4E並不限定於包含由序列編號99之鹼基序列所編碼之序列編號100之胺基酸序列的蛋白質。關於EIF4E，如 上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號99之鹼基序列表示其中一個轉錄變異體之鹼基序列。 EIF4E (eukaryotic translation initiation factor 4E) is known as a protein that constitutes a eukaryotic translation initiation factor 4F complex that recognizes the 7-methylguanosine cap structure at the 5' end of mRNA. EIF4E assists in the initiation of translation by concentrating the ribosome into a 5' end cap structure. The combination of EIF4E and the 4F complex becomes the rate-limiting phase at which translation begins. EIF4E is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_001968.3, NM_001130679.1, NM_001130678.1, XM_006714126.2, XM_006714127.2 (NP_001959.1, NP_001124151.1) , NP_001124150.1, XP_006714189.1, XP_006714190.1), etc.; the number indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human EIF4E gene which is registered in the database as NM_001968.3 is shown in SEQ ID NO: 99, and the amino acid sequence of the human EIF4E protein encoded by the human EIF4E gene is shown in SEQ ID NO: 100. Further, in the present specification, EIF4E is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 100 encoded by the nucleotide sequence of SEQ ID NO: 99. About EIF4E, such as The sequence information is registered in a plurality of registration numbers as described above, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 99 indicates the base sequence of one of the transcribed variants.

已知ILK(integrin linked kinase，整合素連接激酶)係具有激酶樣區域及四個錨蛋白樣重複序列之蛋白質，其藉由在細胞膜與β整合素之細胞質區域結合而控制經由整合素之訊號傳遞。ILK存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_004517.3,NM_001278441.1,NM_001014794.2,NM_001278442.1,NM_001014795.2,XM_005252904.3,XM_005252905.1,XM_011520065.1(NP_004508.1,NP_001265370.1,NP_001014794.1,NP_001265371.1,NP_001014795.1,XP_005252961.1,XP_005252962.1,XP_011518367.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_004517.3而登記於資料庫中之人類ILK基因之鹼基序列示於序列編號101，將該人類ILK基因所編碼之人類ILK蛋白質之胺基酸序列示於序列編號102。再者，於本說明書中，ILK並不限定於因序列編號101之鹼基序列所編碼之序列編號102之胺基酸序列的蛋白質。關於ILK，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號101之鹼基序列表示其中一個轉錄變異體之鹼基序列。 It is known that ILK (integrin linked kinase) is a protein having a kinase-like region and four ankyrin-like repeats, which control signal transmission via integrin by binding to the cytoplasmic region of β-integrin in the cell membrane. . ILK is present in a variety of animals, including humans, and its sequence information is also well known (eg, human: NM_004517.3, NM_001278441.1, NM_001014794.2, NM_001278442.1, NM_001014795.2, XM_005252904.3, XM_005252905.1 , XM_011520065.1 (NP_004508.1, NP_001265370.1, NP_001014794.1, NP_001265371.1, NP_001014795.1, XP_005252961.1, XP_005252962.1, XP_011518367.1), etc.; the number indicates the registration number of the NCBI database, outside the brackets The base sequence, in brackets, is the number of the amino acid sequence). As an example, the nucleotide sequence of the human ILK gene registered as a NM_004517.3 in the database is shown in SEQ ID NO: 101, and the amino acid sequence of the human ILK protein encoded by the human ILK gene is shown in SEQ ID NO: 102. Further, in the present specification, ILK is not limited to the protein of the amino acid sequence of SEQ ID NO: 102 encoded by the nucleotide sequence of SEQ ID NO: 101. Regarding ILK, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 101 indicates the base sequence of one of the transcribed variants.

已知MTCP1(mature T-cell proliferation 1，成熟T細胞增殖蛋白1)係根據與和成熟T細胞之增殖相關之若干t(X；14)易位之相關性而鑑定。該區域具有含有共通啟動子、剪切為編碼兩個不同蛋白質之兩個不同之3'外顯子的5'外顯子的複雜結構。認為上游13kD之蛋白質屬於TCL1家族，其與誘發白血病相關。MTCP1存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_001018025.3(NP_001018025.1)等；編號表示NCBI資料庫之寄存 編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_001018025.3而登記於資料庫中之人類MTCP1基因之鹼基序列示於序列編號103，將該人類MTCP1基因所編碼之人類MTCP1蛋白質之胺基酸序列示於序列編號104。再者，於本說明書中，MTCP1並不限定於包含由序列編號103之鹼基序列所編碼之序列編號104之胺基酸序列的蛋白質。關於MTCP1，有存在複數個轉錄變異體之可能性。序列編號103之鹼基序列表示其中一個轉錄變異體之鹼基序列。 MTCP1 (mature T-cell proliferation 1, mature T cell proliferation protein 1) is known to be identified based on the correlation with several t(X; 14) translocations associated with proliferation of mature T cells. This region has a complex structure containing a common promoter, which is cleaved into a 5' exon encoding two different 3' exons of two different proteins. It is believed that the upstream 13 kD protein belongs to the TCL1 family, which is associated with the induction of leukemia. MTCP1 is present in various animals including humans, and its sequence information is also known (for example, human: NM_001018025.3 (NP_001018025.1); etc.; the number indicates the registration of the NCBI database. Number, the base sequence outside the parentheses, the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human MTCP1 gene registered in the database as NM_001018025.3 is shown in SEQ ID NO: 103, and the amino acid sequence of the human MTCP1 protein encoded by the human MTCP1 gene is shown in SEQ ID NO: 104. Further, in the present specification, MTCP1 is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 104 encoded by the nucleotide sequence of SEQ ID NO: 103. Regarding MTCP1, there is a possibility that a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 103 indicates the base sequence of one of the transcribed variants.

PIK3CA(phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit alpha，4,5-二磷酸磷脂醯肌醇3-激酶觸媒次單元α)係磷脂醯肌醇3-激酶中之110kD之觸媒次單元，利用ATP將PtdIns、PtdIns4P及PtdIns(4，5)P2進行磷酸化。PIK3CA存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_006218.2,XM_006713658.2,XM_011512894.1(NP_006209.2,XP_006713721.1,XP_011511196.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_006218.2而登記於資料庫中之人類PIK3CA基因之鹼基序列示於序列編號105，將該人類PIK3CA基因所編碼之人類PIK3CA蛋白質之胺基酸序列示於序列編號106。再者，於本說明書中，PIK3CA並不限定於包含由序列編號105之鹼基序列所編碼之序列編號106之胺基酸序列的蛋白質。關於PIK3CA，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號105之鹼基序列表示其中一個轉錄變異體之鹼基序列。 PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha, 4,5-diphospholipid phosphoinositide 3-kinase-catalytic subunit α) is a 110kD catalyst in phospholipid inositol 3-kinase In the secondary unit, PtdIns, PtdIns4P, and PtdIns(4,5)P2 are phosphorylated using ATP. PIK3CA is present in various animals including humans, and its sequence information is also known (for example, human: NM_006218.2, XM_006713658.2, XM_011512894.1 (NP_006209.2, XP_006713721.1, XP_011511196.1), etc.; Indicates the registration number of the NCBI database, the base sequence outside the parentheses, and the number of the amino acid sequence in parentheses). As an example, the nucleotide sequence of the human PIK3CA gene registered as a NM_006218.2 in the database is shown in SEQ ID NO: 105, and the amino acid sequence of the human PIK3CA protein encoded by the human PIK3CA gene is shown in SEQ ID NO: 106. Further, in the present specification, PIK3CA is not limited to a protein comprising an amino acid sequence of SEQ ID NO: 106 encoded by the nucleotide sequence of SEQ ID NO: 105. Regarding PIK3CA, as described above, sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 105 indicates the base sequence of one of the transcribed variants.

已知SRF(serum response factor，血清反應因子)係促進細胞增殖及分化之普遍性核蛋白質。SRF屬於轉錄因子之MADS(MCM1,Agamous,Deficiens,and SRF)盒超家族。SRF於標靶基因之啟動子區 域與血清應答因子(SRE)結合。SRF係控制c-fos之諸多前初期基因之活化，而與細胞週期控制、細胞凋亡、細胞成長及細胞分化相關。SRF存在於包括人類在內之各種動物體內，其序列資訊亦為公知(例如，人類：NM_003131.3,NM_001292001.1(NP_003122.1,NP_001278930.1)等；編號表示NCBI資料庫之寄存編號，括號外為鹼基序列，括號內為胺基酸序列之編號)。作為一例，將作為NM_003131.3而登記於資料庫中之人類SRF基因之鹼基序列示於序列編號107，將該人類SRF基因所編碼之人類SRF蛋白質之胺基酸序列示於序列編號108。再者，於本說明書中，SRF並不限定於包含由序列編號107之鹼基序列所編碼之序列編號108之胺基酸序列的蛋白質。關於SRF，如上所述以複數個寄存編號登記序列資訊，存在複數個轉錄變異體。序列編號107之鹼基序列表示其中一個轉錄變異體之鹼基序列。 SRF (serum response factor) is known as a universal nuclear protein that promotes cell proliferation and differentiation. SRF belongs to the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. SRF in the promoter region of the target gene The domain binds to serum response factor (SRE). The SRF system controls the activation of many pre-initial genes of c-fos, which are involved in cell cycle control, apoptosis, cell growth, and cell differentiation. SRF is present in various animals including humans, and its sequence information is also known (for example, human: NM_003131.3, NM_001292001.1 (NP_003122.1, NP_001278930.1), etc.; the number indicates the registration number of the NCBI database, The base sequence is outside the parentheses, and the amino acid sequence number is in parentheses. As an example, the base sequence of the human SRF gene registered as a NM_003131.3 in the database is shown in SEQ ID NO: 107, and the amino acid sequence of the human SRF protein encoded by the human SRF gene is shown in SEQ ID NO: 108. Further, in the present specification, the SRF is not limited to a protein comprising the amino acid sequence of SEQ ID NO: 108 encoded by the nucleotide sequence of SEQ ID NO: 107. Regarding the SRF, as described above, the sequence information is registered with a plurality of registration numbers, and a plurality of transcription variants exist. The nucleotide sequence of SEQ ID NO: 107 indicates the base sequence of one of the transcribed variants.

再者，如以上般，關於GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF，可藉由具體之鹼基序列及胺基酸序列而特定，但必須考慮到於生物個體間產生鹼基序列或胺基酸序列之變異之可能性(包含多型)。 Furthermore, as described above, regarding GST-π, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA and SRF can be specified by specific base sequences and amino acid sequences, but it is necessary to take into account the possibility of generating base sequence or amino acid sequence variation between biological individuals (including Multi-type).

即，GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、 MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF並不限定於與資料庫中所登記之胺基酸序列具有相同序列之蛋白質，亦包括相對於同序列具有1個或2個以上，典型而言為1個或數個、例如1個、2個、3個、4個、5個、6個、7個、8個、9個或10個胺基酸不同之序列，且具有與GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF同等之功能者。 That is, GST-π, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2 MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA and SRF are not limited to those in the database. The registered amino acid sequence has the same sequence of proteins, and also includes one or more than the same sequence, typically 1 or several, for example, 1, 2, 3, 4, 5 Sequence of 6, 6 or 8, 8 or 10 amino acids, and with GST-π, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF are equivalent functions.

又，GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF亦包括編碼相對於上述具體之鹼基序列具有70%以上、80%以上、90%以上、95%以上或97%以上之同一性之鹼基序列，且具有與GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、 BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF同等之功能之蛋白質者。 Further, GST-π, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1 PIK3CA and SRF also include a base sequence encoding 70% or more, 80% or more, 90% or more, 95% or more, or 97% or more of the identity with respect to the above specific base sequence, and having GST-π, ATM , CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1 BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA and A protein with the same function as SRF.

再者，關於GST-π、ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MYLK、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF之具體功能，如上所述。 Furthermore, regarding GST-π, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MYLK, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, The specific functions of MTCP1, PIK3CA and SRF are as described above.

再者，於本說明書中，「於本說明書中使用之情形時」、「於本說明書中使用」、「於本說明書中」、「本說明書中所記載之」等表述只要未特別說明，則意指其後所記載之內容適用於本說明書中所記載之全部發明。又，只要未另作定義，則本說明書中使用之全部技術用語及科學用語具有與從業者之通常理解相同之含義。本說明書中參照之全部專利、公報及其他出版物之全部內容係引用至本說明書中。 In addition, in the present specification, the expression "in the case of use in the present specification", "in the present specification", "in the present specification", "described in the present specification", etc., unless otherwise specified, It is intended that the contents described hereinafter apply to all inventions described in the present specification. Further, all technical terms and scientific terms used in the specification have the same meaning as commonly understood by the practitioner unless otherwise defined. The entire contents of all patents, publications and other publications referred to in this specification are hereby incorporated by reference.

對於本說明書中使用之「抑制GST-π之藥物」並無限定，例如包括抑制GST-π之產生及/或活性之藥物，或促進GST-π之分解及/或減活之藥物等。作為抑制GST-π之產生之藥物，並不限定於此，例如亦可列舉針對編碼GST-π之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等之載體等。 The "drug suppressing GST-π" used in the present specification is not limited, and includes, for example, a drug that inhibits the production and/or activity of GST-π, or a drug that promotes decomposition and/or deactivation of GST-π. The drug for inhibiting the production of GST-π is not limited thereto, and examples thereof include an RNAi molecule, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and the like for DNA encoding GST-π. Carriers, etc.

又，作為抑制GST-π之藥物，亦可使用對GST-π發揮作用之任何化合物。作為此種化合物，可使用有機化合物(胺基酸、多肽或其衍生物、低分子化合物、糖、高分子化合物等)、無機化合物等。又， 此種化合物可為天然物質及非天然物質之任一者。作為多肽之衍生物，可列舉附加修飾基而獲得之修飾多肽、藉由改變胺基酸殘基而獲得之變異體多肽等。進而，此種化合物可為單一化合物，亦可為化合物庫、基因庫之表現產物、細胞萃取物、細胞培養上清液、醱酵微生物產生物、海洋生物萃取物、植物萃取物等。即，「抑制GST-π之藥物」並不限定於RNAi分子等核酸，亦包括任何化合物。 Further, as the drug for inhibiting GST-π, any compound which acts on GST-π can also be used. As such a compound, an organic compound (amino acid, a polypeptide or a derivative thereof, a low molecular compound, a sugar, a polymer compound, or the like), an inorganic compound, or the like can be used. also, Such a compound may be either natural or non-natural. Examples of the derivative of the polypeptide include a modified polypeptide obtained by adding a modifying group, a variant polypeptide obtained by changing an amino acid residue, and the like. Further, such a compound may be a single compound, or may be a compound library, a gene product of a gene bank, a cell extract, a cell culture supernatant, a fermented microorganism product, a marine organism extract, a plant extract, or the like. That is, the "drug suppressing GST-π" is not limited to a nucleic acid such as an RNAi molecule, and includes any compound.

具體而言，作為抑制GST-π之活性之藥物，並不限定於此，例如亦可列舉與GST-π結合之物質、例如麩胱甘肽、麩胱甘肽類似物(例如WO 95/08563、WO 96/40205、WO 99/54346、非專利文獻4等中所記載者)、酮洛芬(非專利文獻2)、吲哚美辛(Hall et al.,Cancer Res.1989；49(22)：6265-8)、利尿酸、piloprost(Tew et al.,Cancer Res.1988；48(13)：3622-5)、抗GST-π抗體、GST-π之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Specifically, the drug which inhibits the activity of GST-π is not limited thereto, and examples thereof include substances which bind to GST-π, such as glutathione and glutathione analogs (for example, WO 95/08563). , WO 96/40205, WO 99/54346, Non-Patent Document 4, etc.), ketoprofen (Non-Patent Document 2), indomethacin (Hall et al., Cancer Res. 1989; 49 (22) ): 6265-8), uric acid, piloprost (Tew et al., Cancer Res. 1988; 48 (13): 3622-5), anti-GST-π antibody, dominant negative variant of GST-π, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

作為抑制GST-π之產生或活性之藥物，就特異性高、或副作用之可能性度之方面而言，較佳為針對編碼GST-π之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等之載體。 As a drug for inhibiting the production or activity of GST-π, an RNAi molecule, a ribozyme, an antisense nucleic acid, or a DNA encoding a DNA encoding GST-π is preferred in terms of high specificity or possibility of side effects. /RNA chimeric polynucleotides and vectors expressing the same.

GST-π之抑制與未使GST-π抑制劑發揮作用之情形相比，可藉由在細胞中抑制GST-π之表現或活性而決定。GST-π之表現可藉由已知之任意方法進行評價，並無限定，例如利用抗GST-π抗體之免疫沈降法、EIA、ELISA、IRA、IRMA、西方墨點法、免疫組織化學法、免疫細胞化學法、流式細胞儀法、利用編碼GST-π之核酸或其特有之片段或該核酸之轉錄產物(例如，mRNA)或對剪切產物特異性地進行雜交之核酸的各種雜交法、北方墨點法、南方墨點法、各種PCR法等。 The inhibition of GST-π can be determined by inhibiting the expression or activity of GST-π in cells compared to the case where GST-π inhibitor is not acted upon. The expression of GST-π can be evaluated by any known method, and is not limited, for example, immunoprecipitation using anti-GST-π antibody, EIA, ELISA, IRA, IRMA, Western blot, immunohistochemistry, immunization Cytochemistry, flow cytometry, various hybridization methods using a nucleic acid encoding a GST-π or a fragment thereof or a transcription product of the nucleic acid (for example, mRNA) or a nucleic acid that specifically hybridizes to a cleavage product, Northern ink point method, southern ink point method, various PCR methods, etc.

又，關於GST-π之活性，可藉由已知之任意方法、例如免疫沈降法、西方墨點法、質量分析法、下拉法、表面電漿子共振(SPR)法等對GST-π之已知之活性進行分析而評價，該已知活性並無限定，例如 為Raf-1(尤其是磷酸化Raf-1)或EGFR(尤其是磷酸化EGFR)等之與蛋白質之結合性等。 Further, regarding the activity of GST-π, GST-π can be used by any known methods such as immunoprecipitation, Western blotting, mass spectrometry, down-draw, surface plasmon resonance (SPR), and the like. The known activity is evaluated by analysis, and the known activity is not limited, for example It is a protein-binding property such as Raf-1 (especially phosphorylated Raf-1) or EGFR (especially phosphorylated EGFR).

本說明書中使用之「抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物」並無限定，例如包括抑制該蛋白質之產生及/或活性之藥物、或促進該蛋白質之分解及/或減活之藥物等。作為抑制該蛋白質之產生之藥物，並不限定於此，例如可列舉：針對編碼該恆常性維持相關蛋白質之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等之載體等。又，作為抑制該恆常性維持相關蛋白質之活性之藥物、促進該恆常性維持相關蛋白質之分解及/或減活之藥物，亦可使用對該蛋白質發揮作用之任何化合物。作為此種化合物，可使用有機化合物(胺基酸、多肽或其衍生物、低分子化合物、糖、高分子化合物等)、無機化合物等。又，此種化合物可為天然物質及非天然物質之任一者。作為多肽之衍生物，可列舉附加修飾基而獲得之修飾多肽、藉由改變胺基酸殘基而獲得之變異體多肽等。進而，此種化合物可為單一化合物，亦可為化合物庫、基因庫之表現產物、細胞萃取物、細胞培養上清液、醱酵微生物產生物、海洋生物萃取物、植物萃取物等。即，「抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物」不限定於RNAi分子等核酸，亦包括任何化合物。 The "inhibiting drug which exhibits a synthetic lethality to maintain a related protein when it is inhibited together with GST-π" as used in the present specification is not limited, and includes, for example, a drug which inhibits the production and/or activity of the protein, Or a drug that promotes decomposition and/or deactivation of the protein. The drug for inhibiting the production of the protein is not limited thereto, and examples thereof include an RNAi molecule, a ribozyme, an antisense nucleic acid, and a DNA/RNA chimeric polynucleotide which encode DNA for the constantity-maintaining related protein. And the expression of such vectors and the like. Further, as a drug which suppresses the activity of the constant-maintaining related protein, and a drug which promotes the decomposition and/or deactivation of the related protein by the constantity, any compound which acts on the protein may be used. As such a compound, an organic compound (amino acid, a polypeptide or a derivative thereof, a low molecular compound, a sugar, a polymer compound, or the like), an inorganic compound, or the like can be used. Further, such a compound may be either a natural substance or a non-natural substance. Examples of the derivative of the polypeptide include a modified polypeptide obtained by adding a modifying group, a variant polypeptide obtained by changing an amino acid residue, and the like. Further, such a compound may be a single compound, or may be a compound library, a gene product of a gene bank, a cell extract, a cell culture supernatant, a fermented microorganism product, a marine organism extract, a plant extract, or the like. In other words, "a drug that suppresses the expression of a synthetic lethality-maintaining related protein when it is suppressed together with GST-π" is not limited to a nucleic acid such as an RNAi molecule, and includes any compound.

更具體而言，若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制p21之活性之藥物，並不限定於此，例如可列舉：於促進p21蛋白之蛋白酶體分解之同時亦抑制CDC2、CDK2及CDK5之酶活性的作為低分子化合物之丁內酯I(Sax et.al,Cell Cycle,Jan；1(1)：90-6,2002)、CD-1小鼠之神經細胞或寡樹突神經膠細胞(oligodendrocyte)中特異性地抑制p21之表現的作為親精神藥之喹硫平(Kondo et.al,Transl.Psychiatry,Apr 2；3：e243,2013)、與p53、p27或Akt 無關而特異性地抑制p21且抑制針對Raf、VEGFR或PDGFR等之多激酶的作為低分子化合物之索拉非尼(Inoue et.al,Cancer Biology & Therapy,12：9,827-836,2011)、與p53或Akt無關而特異性地抑制p21的作為低分子化合物之UC2288(Wettersten et.al,Cancer Biology & Therapy,14(3),278-285,2013)、針對編碼p21之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗p21抗體、p21之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 More specifically, the drug which inhibits the activity of p21 is not limited to this, and is a drug which inhibits the activity of p21, and is, for example, promotes p21 protein. The butyrolactone I as a low molecular compound which inhibits the enzymatic activity of CDC2, CDK2 and CDK5 (Sax et. al, Cell Cycle, Jan; 1(1): 90-6, 2002), CD -1 quetiapine as a psychotropic drug that specifically inhibits the expression of p21 in nerve cells or oligodendrocytes of mice (Kondo et. al, Transl. Psychiatry, Apr 2; 3: e243) , 2013), with p53, p27 or Akt Sorafenib (Inoue et. al, Cancer Biology & Therapy, 12:9, 827-836, 2011), which is a low molecular compound that inhibits p21 independently and inhibits multiple kinases such as Raf, VEGFR or PDGFR, and UC2288 as a low molecular compound that specifically inhibits p21 regardless of p53 or Akt (Wettersten et. al, Cancer Biology & Therapy, 14(3), 278-285, 2013), RNAi molecule against DNA encoding p21, nuclear An enzyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and a vector expressing the same, an anti-p21 antibody, a dominant negative variant of p21, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制RNPC1之活性之藥物，並不限定於此，例如可列舉：針對編碼RNPC1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現之載體、抗RNPC1抗體、RNPC1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of RNPC1 is not limited to this, and is a drug which inhibits the activity of RNPC1, and is, for example, an RNAi molecule encoding DNA of RNPC1, Ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, and expression vector, anti-RNPC1 antibody, dominant negative variant of RNPC1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制CCNL1之活性之藥物，並不限定於此，例如可列舉：針對編碼CCNL1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗CCNL1抗體、CCNL1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of CCNL1 is not limited to this, and is a drug which inhibits the activity of CCNL1, and is, for example, an RNAi molecule for DNA encoding CCNL1, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-CCNL1 antibodies, dominant negative variants of CCNL1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制MCM8之活性之藥物，並不限定於此，例如可列舉：針對編碼MCM8之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MCM8抗體、MCM8之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of MCM8 is not limited to this, and is a drug which inhibits the activity of MCM8, and is, for example, an RNAi molecule for DNA encoding MCM8, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MCM8 antibodies, dominant negative variants of MCM8, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制CCNB3之活性之藥物，並不限定於此，例如可列舉：針對編碼CCNB3之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗CCNB3抗體、CCNB3之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of CCNB3 is not limited to this, and is a drug which inhibits the activity of CCNB3, and is, for example, an RNAi molecule for DNA encoding CCNB3, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-CCNB3 antibodies, dominant negative variants of CCNB3, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制MCMDC1之活性之藥物，並不限定於此，例如可列舉：針對編碼MCMDC1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MCMDC1抗體、MCMDC1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of MCMDC1 is not limited to this, and is a drug which inhibits the activity of MCMDC1, and is, for example, an RNAi molecule encoding DNA of MCMDC1, for example, which is inhibited by GST-π. Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MCMDC1 antibodies, dominant negative variants of MCMDC1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制ATM之活性之藥物，並不限定於此，例如可列舉：選擇性地抑制ATM及ATR之激酶活性的作為低分子化合物之CGK 733(Won et.al,Nat.Chem.Biol.2,369,2006)、選擇性地抑制ATM之激酶活性的作為低分子化合物之KU-55933(Lau et.al,Nat.Cell Biol.7,493,2005)、KU-60019(Zirkin et.al,J Biol Chem.Jul 26；288(30)：21770-83,2013)、CP-466722(Rainey et.al,Cancer Res.Sep 15；68(18)：7466-74,2008)、針對編碼ATM之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ATM抗體、ATM之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of ATM is not limited to this, and is a drug which inhibits the activity of ATM, and is, for example, a kinase which selectively inhibits ATM and ATR, for example, which is inhibited by GST-π. Active KUK 733 as a low molecular compound (Won et. al, Nat. Chem. Biol. 2, 369, 2006), KU-55933 as a low molecular compound that selectively inhibits the kinase activity of ATM (Lau et.al, Nat .Cell Biol. 7, 493, 2005), KU-60019 (Zirkin et. al, J Biol Chem. Jul 26; 288(30): 21770-83, 2013), CP-466722 (Rainey et. al, Cancer Res. Sep 15;68(18):7466-74,2008), RNAi molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-ATM antibodies against DNA encoding ATM , dominant negative variants of ATM, etc. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制CDC25A之活性之藥物，並不限定於此，例如可列舉：抑制人類CDC25A、人類CDC25B及人類CDC25C之各自脫磷酸化 酶活性的作為低分子化合物之NSC95397(Lazo JS et al.,Mol.Pharmacol.61：720-728,2002)、人類CDC25A、人類CDC25B、人類CDC25C及抑制作為人類酪胺酸脫磷酸化酶之PTB1B之各自脫磷酸化酶活性的作為低分子化合物之SC alpha alpha delta 09(Rice,R.L.et al.,Biochemistry 36(50)：15965-15974,1997)、針對編碼CDC25A之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗CDC25A抗體、CDC25A之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of CDC25A is not limited to this, and is a drug which inhibits the activity of CDC25A, and is exemplified by inhibition of human CDC25A, human CDC25B, and human CDC25C. Dephosphorylation Enzyme activity as a low molecular compound NSC95397 (Lazo JS et al., Mol. Pharmacol. 61: 720-728, 2002), human CDC25A, human CDC25B, human CDC25C and inhibition of PTB1B as a human tyrosine dephosphorylation enzyme SC alpha alpha delta 09 as a low molecular compound of each dephosphorylation enzyme activity (Rice, RL et al., Biochemistry 36 (50): 15965-15974, 1997), RNAi molecule against DNA encoding CDC25A, ribozyme , antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-CDC25A antibodies, dominant negative variants of CDC25A, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制PRKDC之活性之藥物，並不限定於此，例如可列舉：針對編碼PRKDC之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗PRKDC抗體、PRKDC之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 In the cell cycle-regulated protein which exhibits the synthesis of lethality, the drug which inhibits the activity of PRKDC is not limited thereto, and examples thereof include RNAi molecules for DNA encoding PRKDC, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-PRKDC antibodies, dominant negative variants of PRKDC, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制RBBP8之活性之藥物，並不限定於此，例如可列舉：針對編碼PRBBP8之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗RBBP8抗體、RBBP8之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of RBBP8 is not limited to this, and is a drug which inhibits the activity of RBBP8, and is, for example, an RNAi molecule for DNA encoding PRBBP8, for example, which is inhibited by GST-π. Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-RBBP8 antibodies, dominant negative variants of RBBP8, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制SKP2之活性之藥物，並不限定於此，例如可列舉：針對編碼SKP2之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗SKP2抗體、SKP2之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 In the cell cycle-regulated protein which exhibits the synthesis of lethality, the drug which inhibits the activity of SKP2 is not limited thereto, and examples thereof include, for example, an RNAi molecule encoding DNA of SKP2, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-SKP2 antibodies, dominant negative variants of SKP2, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制MCM10之活性之藥物，並不限定於此，例如可列舉：針對編碼MCM10之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MCM10抗體、MCM10之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of MCM10 is not limited to this, and is a drug which inhibits the activity of MCM10, and is, for example, an RNAi molecule for DNA encoding MCM10, for example, which is inhibited by GST-π. Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MCM10 antibodies, dominant negative variants of MCM10, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制CENPH之活性之藥物，並不限定於此，例如可列舉：針對編碼CENPH之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗CENPH抗體、CENPH之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of CENPH is not limited to the one which exhibits the activity of inhibiting CENPH, and is, for example, an RNAi molecule for DNA encoding CENPH, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-CENPH antibodies, dominant negative variants of CENPH, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制BRSK1之活性之藥物，並不限定於此，例如可列舉：針對編碼BRSK1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗BRSK1抗體、BRSK1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of BRSK1 among the cell cycle-regulated proteins which exhibits the synthesis of lethality is not limited thereto, and examples thereof include RNAi molecules encoding DNA of BRSK1, Ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-BRSK1 antibodies, dominant negative variants of BRSK1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質之中，作為抑制MYLK之活性之藥物，並不限定於此，例如可列舉：除了抑制各種蛋白激酶(PKA及PKC等)之活性以外亦抑制MYLK之活性的作為低分子化合物之HA-100二鹽酸鹽(Gerard et.al,J Clin Invest.Jan；77(1)：61-5.1986)、除了抑制各種蛋白激酶(PKA、PKC、PKG、CaMK、CaMKII及磷酸化酶激酶等)之活性以外亦抑制MYLK之活性的作為低分子化合物之星形孢菌素(Tamaoki et.al,Biochem.Biophys.Res.Commun.135：397-402.1986)、為PKC之選擇性抑制劑 且亦抑制MYLK之活性的作為低分子化合物之鈣磷酸結合蛋白C(Kobayashi et.al,Biochem.Biophys.Res.Commun.159：548-553.1989)、為酪胺酸激酶抑制劑且亦抑制MYLK之活性的作為低分子化合物之白皮杉醇(Oliver et.al,J.Biol.Chem.269：29697-29703.1994)、除了抑制各種酪蛋白激酶及蛋白激酶之活性以外亦抑制MYLK之活性的作為低分子化合物之A-3鹽酸鹽(Inagaki et.al,Mol.Pharmacol.29,577.1986)、細胞透過性之絲胺酸/蘇胺酸激酶抑制劑亦抑制MYLK之活性之作為低分子化合物之H-7二鹽酸鹽(Kawamoto et.al,Biochem.Biophys.Res.Commun.125：258-264.1984)、除了抑制各種蛋白激酶(PKA及PKC等)之活性以外亦抑制MYLK之活性的作為低分子化合物之H-9鹽酸鹽(Wolf et.al,J.Biol.Chem.260：15718-15722.1985)、為鈣調蛋白(CaM)拮抗劑且亦抑制MYLK之活性的作為低分子化合物之W-5(Hidaka et.al,Mol.Pharmacol.20：571-578.1981)、為鈣調蛋白(CaM)拮抗劑亦抑制MYLK之活性的作為低分子化合物之W-7(Hidaka et.al,Proc.Natl.Acad.Sci.U.S.A.78：4354-4357.1981)、除了抑制各種蛋白激酶(PKA及PKC等)之活性以外亦抑制MYLK之活性的作為低分子化合物之W-13異構物鹽酸鹽(Hidaka et.al,Proc.Natl.Acad.Sci.U.S.A.78：4354-4357.1981)、除了抑制各種蛋白激酶(PKA及PKC等)之活性以外亦抑制MYLK之活性的作為低分子化合物之ML-7二鹽酸鹽(Saitoh et.al,J.Biol.Chem.262：7796-7801.1987)、選擇性地抑制MYLK及CaMK的作為低分子化合物之ML-9(Saitoh et.al,Biochem.Biophys.Res.Commun.140：280-287.1986)、除了抑制各種酪蛋白激酶及蛋白激酶之活性以外亦抑制MYLK之活性的作為低分子化合物之楊梅黃酮(Hagiwara et.al,Biochem.Pharmacol.37：2987-2992.1988)、為細胞透過性之鈣調蛋白(CaM)拮抗劑且亦抑制MYLK之活性的作為低分子化合物之E6小檗胺(Hu et.al,Biochem. Pharmacol.Oct 20；44(8)：1543-7.1992)、除了抑制各種蛋白激酶之活性以外亦抑制MYLK之活性的作為低分子化合物之K-252a(Kase et.al,J.Antibiot.39：1059-1065.1986)、除了抑制各種蛋白激酶之活性以外亦抑制MYLK之活性的作為低分子化合物之K-252b(Nakanishi et.al,J.Antibiot.39：1066-1071.1986)、為c-Src抑制劑且亦抑制MYLK之活性的作為低分子化合物之細格菌素(Rosett et.al,Biochem.J.67：390-400.1957)、針對編碼MYLK之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MYLK抗體、MYLK之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 The drug which inhibits the activity of MYLK is not limited to this, and is a drug which inhibits the activity of MYLK, for example, in addition to inhibition of various protein kinases (PKA and PKC). HA-100 dihydrochloride as a low molecular compound which inhibits the activity of MYLK in addition to the activity of (etc.) (Gerard et. al, J Clin Invest. Jan; 77(1): 61-5.1986), in addition to inhibition of various protein kinases (In addition to the activities of PKA, PKC, PKG, CaMK, CaMKII, and phosphorylase, etc.), Staphylococcus as a low molecular compound that inhibits the activity of MYLK (Tamaoki et. al, Biochem. Biophys. Res. Commun. 135:397-402.1986), a selective inhibitor of PKC Calcium phosphate-binding protein C (Kobayashi et. al, Biochem. Biophys. Res. Commun. 159: 548-553. 1989), which is a low molecular compound which also inhibits the activity of MYLK, is a tyrosine kinase inhibitor and also inhibits MYLK. Active as a low molecular compound of paclitaxel (Oliver et. al, J. Biol. Chem. 269: 29697-29703. 1994), in addition to inhibiting the activity of various casein kinases and protein kinases, also inhibits the activity of MYLK as low The molecular compound A-3 hydrochloride (Inagaki et. al, Mol. Pharmacol. 29, 577. 1986), cell permeable serine/threonine kinase inhibitor also inhibits the activity of MYLK as a low molecular compound H-7 Dihydrochloride (Kawamoto et. al, Biochem. Biophys. Res. Commun. 125: 258-264. 1984), in addition to inhibiting the activity of various protein kinases (PKA and PKC, etc.), also inhibits the activity of MYLK as a low molecular compound. H-9 hydrochloride (Wolf et. al, J. Biol. Chem. 260: 15718-15722. 1985), a low molecular compound W-5 (which is a calmodulin (CaM) antagonist and also inhibits the activity of MYLK ( Hidaka et.al, Mol. Pharmacol. 20: 571-578.1981), a calmodulin (CaM) antagonist also inhibits MYLK As a low molecular compound W-7 (Hidaka et. al, Proc. Natl. Acad. Sci. USA 78: 4354-4357. 1981), in addition to inhibiting the activity of various protein kinases (PKA and PKC, etc.), it also inhibits MYLK. Active W-13 isomer hydrochloride as a low molecular compound (Hidaka et. al, Proc. Natl. Acad. Sci. USA 78: 4354-4357. 1981), in addition to inhibition of various protein kinases (PKA and PKC, etc.) ML-7 dihydrochloride as a low molecular compound which inhibits the activity of MYLK in addition to activity (Saitoh et. al, J. Biol. Chem. 262:7796-7801.1987), selectively inhibits MYLK and CaMK as low molecules ML-9 (Saitoh et. al, Biochem. Biophys. Res. Commun. 140: 280-287. 1986), a compound of low molecular weight which inhibits the activity of MYLK in addition to the activity of various casein kinases and protein kinases Flavonoids (Hagiwara et. al, Biochem. Pharmacol. 37: 2987-2992. 1988), E6 berbamine, a low molecular compound that is a cell-permeable calmodulin (CaM) antagonist and also inhibits the activity of MYLK (Hu et al) .al,Biochem. Pharmacol. Oct 20; 44(8): 1543-7. 1992) K-252a as a low molecular compound which inhibits the activity of MYLK in addition to the activity of various protein kinases (Kase et. al, J. Antibiot. 39: 1059) -1065.1986), a low molecular compound K-252b (Nakanishi et. al, J. Antibiot. 39: 1066-1071.1986), which inhibits the activity of various protein kinases and also inhibits the activity of MYLK, is a c-Src inhibitor and As a low molecular compound statin (Rosett et. al, Biochem. J. 67: 390-400.1957), which inhibits the activity of MYLK, RNAi molecule, ribozyme, antisense nucleic acid, DNA/ for DNA encoding MYLK RNA chimeric polynucleotides, and vectors expressing the same, anti-MYLK antibodies, dominant negative variants of MYLK, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

另一方面，若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制AATF之活性之藥物，並不限定於此，例如可列舉：針對編碼AATF之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗AATF抗體、AATF之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 On the other hand, among the anti-apoptosis-related proteins which are shown to be inhibited by the combination of GST-π, the drug which inhibits the activity of AATF is not limited to this, and for example, it is exemplified for encoding AATF. RNAi molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-AATF antibodies, dominant negative variants of AATF, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制ALOX12之活性之藥物，並不限定於此，例如可列舉：針對編碼ALOX12之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ALOX12抗體、ALOX12之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the proteins which inhibit the activity of ALOX12, the anti-apoptosis-related protein which exhibits the synthesis of lethality is not limited to this. For example, RNAi encoding DNA encoding ALOX12 is exemplified. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-ALOX12 antibodies, dominant negative variants of ALOX12, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制ANXA1之活性之藥物，並不限定於此，例如可列舉：針對編碼ANXA1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ANXA1抗體、 ANXA1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of ANXA1 is not limited thereto, and examples thereof include RNAi for DNA encoding ANXA1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-ANXA1 antibodies, Dominant negative variants of ANXA1, etc. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制ANXA4之活性之藥物，並不限定於此，例如可列舉：針對編碼ANXA4之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ANXA4抗體、ANXA4之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the proteins which inhibit the activity of ANXA4, the anti-apoptosis-related protein which exhibits the synthesis of lethality is not limited to this. For example, RNAi encoding the DNA encoding ANXA4 can be mentioned. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-ANXA4 antibodies, dominant negative variants of ANXA4, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制API5之活性之藥物，並不限定於此，例如可列舉：針對編碼API5之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗API5抗體、API5之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptosis-related proteins which are shown to be inhibited by GST-π, the drug which inhibits the activity of API5 is not limited thereto, and examples thereof include RNAi for DNA encoding API5. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-API5 antibodies, dominant negative variants of API5, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制ATF5之活性之藥物，並不限定於此，例如可列舉：針對編碼ATF5之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ATF5抗體、ATF5之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of ATF5 is not limited thereto, and examples thereof include RNAi for DNA encoding ATF5. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-ATF5 antibodies, dominant negative variants of ATF5, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制AVEN之活性之藥物，並不限定於此，例如可列舉：針對編碼AVEN之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗AVEN抗體、AVEN之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of AVEN is not limited thereto, and examples thereof include RNAi for DNA encoding AVEN. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-AVEN antibodies, dominant negative variants of AVEN, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制AZU1之活性之藥物，並不限定於此，例如可列舉：針對編碼AZU1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗AZU1抗體、AZU1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of AZU1 is not limited thereto, and examples thereof include RNAi for DNA encoding AZU1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-AZU1 antibodies, dominant negative variants of AZU1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制BAG1之活性之藥物，並不限定於此，例如可列舉：針對編碼BAG1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗BAG1抗體、BAG1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of BAG1 is not limited thereto, and examples thereof include RNAi for DNA encoding BAG1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-BAG1 antibodies, dominant negative variants of BAG1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制BCL2L1之活性之藥物，並不限定於此，例如可列舉：針對編碼BCL2L1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗BCL2L1抗體、BCL2L1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptosis-related proteins which are shown to inhibit the activity of BCL2L1, the drug which inhibits the activity of BCL2L1 is not limited thereto, and examples thereof include RNAi for DNA encoding BCL2L1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-BCL2L1 antibodies, dominant negative variants of BCL2L1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制BFAR之活性之藥物，並不限定於此，例如可列舉：針對編碼BFAR之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗BFAR抗體、BFAR之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the proteins which inhibit the activity of BFAR, the anti-apoptosis-related protein which exhibits the synthesis of lethality is not limited thereto, and examples thereof include RNAi for DNA encoding BFAR. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-BFAR antibodies, dominant negative variants of BFAR, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制CFLAR之活性之藥物，並不限定於此，例如可 列舉：針對編碼CFLAR之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗CFLAR抗體、CFLAR之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of CFLAR is not limited to this, and is not limited thereto, for example, if it is inhibited together with GST-π. Listed are: RNAi molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-CFLAR antibodies, dominant negative variants of CFLAR, and the like, which encode DNA of CFLAR. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制IL2之活性之藥物，並不限定於此，例如可列舉：針對編碼IL2之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗IL2抗體、IL2之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of IL2 is not limited thereto, and examples thereof include RNAi for DNA encoding IL2. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-IL2 antibodies, dominant negative variants of IL2, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MALT1之活性之藥物，並不限定於此，例如可列舉：針對編碼MALT1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MALT1抗體、MALT1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of MALT1 is not limited thereto, and examples thereof include RNAi for DNA encoding MALT1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MALT1 antibodies, dominant negative variants of MALT1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MCL1之活性之藥物，並不限定於此，例如，可列舉作為慢性骨髓性白血病之治療藥承認之高三尖杉酯鹼(omasetaxine mepesuccinate)、針對編碼MCL1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MCL1抗體、MCL1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of MCL1 is not limited thereto, and for example, it can be cited as a treatment for chronic myeloid leukemia. Medicaxine mepesuccinate, RNAi molecule encoding DNA of MCL1, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, and vector expressing the same, anti-MCL1 antibody, Dominant negative variants of MCL1, etc. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MKL1之活性之藥物，並不限定於此，例如可列舉：針對編碼MKL1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MKL1抗體、MKL1 之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of MKL1 is not limited thereto, and examples thereof include RNAi for DNA encoding MKL1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MKL1 antibodies, MKL1 Dominant negative variants, etc. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MPO之活性之藥物，並不限定於此，例如可列舉：針對編碼MPO之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MPO抗體、MPO之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptosis-related proteins which are shown to be inhibited by GST-π, the drug which inhibits the activity of MPO is not limited thereto, and examples thereof include RNAi for DNA encoding MPO. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MPO antibodies, dominant negative variants of MPO, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MTL5之活性之藥物，並不限定於此，例如可列舉：針對編碼MTL5之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MTL5抗體、MTL5之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of MTL5 is not limited thereto, and examples thereof include RNAi for DNA encoding MTL5. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MTL5 antibodies, dominant negative variants of MTL5, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MYBL2之活性之藥物，並不限定於此，例如可列舉：針對編碼MYBL2之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MYBL2抗體、MYBL2之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the anti-apoptotic proteins involved in the synthesis of lethality, the drug which inhibits the activity of MYBL2 is not limited thereto, and for example, RNAi encoding DNA encoding MYBL2 is exemplified. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MYBL2 antibodies, dominant negative variants of MYBL2, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關蛋白質之中，作為抑制MYO18A之活性之藥物，並不限定於此，例如可列舉：針對編碼MYO18A之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MYO18A抗體、MYO18A之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the proteins which inhibit the activity of MYO18A, the anti-apoptosis-related protein which exhibits the synthesis of lethality is not limited thereto, and examples thereof include RNAi for DNA encoding MYO18A. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MYO18A antibodies, dominant negative variants of MYO18A, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

另一方面，若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制MTOR之活性之藥物，並不限定於此，例如可列舉：為巨環內酯系之免疫抑制劑且抑制MTOR之活性的作為低分子化合物之雷帕黴素(Chang et.al,Trends Pharmacol.Sci.12：218-223.1991)、為源自雷帕黴素之巨環內酯系之免疫抑制劑且抑制MTOR之活性的作為低分子化合物之依維莫司(Weisblum et.al,Br.Med.Bull.40：47-53.1984)、為PI3K酪胺酸激酶抑制劑且抑制MTOR之活性的作為低分子化合物之BEZ235(Maira et.al,Mol.Cancer Ther.7(7)：1851-1863.2008)、選擇性地抑制MTOR之激酶活性的作為低分子化合物之AZD8055(Huang et.al,J Biol Chem.Nov 18；286(46)：40002-12.2011)、為吡啶呋喃嘧啶化合物且抑制DNA-PK、PI3K及MTOR之激酶活性的作為低分子化合物之PI-103(Demyanets et al.2010.Basic Res Cardiol.Mar；106(2)：217-31.2011)、及氯硝柳胺(Balgi et.al,PLoS One.Sep 22；4(9)：e7124.2009)、PP242(Bao et al.J.Cell Biol.210(7)：1153-64.2015)、知母皂苷AIII(King et.al,PLoS One.Sep 30；4(9)：e7283 2009)、KU 0063794(Garcia-Martinez et al.Biochem.J.421(1)：29-42.2009)、AZD2014(Guichard et al.Mol.Cancer.Ther.14(11)：2508-18.2015)、替西羅莫司(Raymond et al.J.Clin.Oncol.22：2336-2347.2004)、Palomid 529(Xue et al.Cancer Res.68(22)：9551-7.2008)、漆樹黃酮(Suh et.al,Carcinogenesis.Aug；31(8)：1424-332010)、GDC-0980(Wallin et al.Mol.Cancer Ther.10(12)：2426-36.2011)、SF1126(Garlich et al.Cancer Res.68(1)：206-15.2008)、CH5132799(Tanaka et al.Clin Cancer Res.17(10)：3272-81.2011)、WYE-354(Yu et al.Cancer Res.69(15)：6232-40.2009)、Compound 401(Ballou et al.J.Biol.Chem.282,24463.2007)、雷達莫司(Gadducci et al.：Gynecol.Endocrinol.24,239.2008)、GSK 1059615(Steven et al. ACS.Med.Chem.Lett.1(1)：39-43 2010)、PF-04691502(Yuan et al.Mol.Cancer Ther.10(11)：2189-99.2011)、PP121(Apsel et al.Nat.Chem.Biol.4(11)：691-9.2008)、OSI-027(Bhaqwat et al.Mol.Cancer Ther.10(8)：1394-406.2011)、WYE-125132(Yu et al.Cancer Res.70(2)：621-31.2010)、佐他莫司(Baldo et al.2008.Curr.Cancer Drug Targets.8(8)：647-65.2008)、WAY-600(Yu et al.Cancer Res.69(15)：6232-40.2009)、WYE-687(Yu et al.Cancer Res.69(15)：6232-40.2009)、PKI-179(Venkatesan et al.Bioorg.Med.Chem.Lett.20(19)：5869-73.2010)、PF-05212384(Akintunde et al.J.Hematol.Oncol.6：88.2013)、CAY10626(Rameh et al.J.Biol.Chem.274：8347-8350.1999)、NVP-BGT226(Chang et al.Clin.Cancer Res.17(22)：7116-26.2011)、XL-147衍生物1(Akintunde et al.J.Hematol.Oncol.6：88.2013)、XL 388(Eduardo et al.Mol Cancer Ther.10(3)：395-403.2011)、Torin 1(Liu et al.J.Med.Chem.53(19)：7146-55.2010)、針對編碼MTOR之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MTOR抗體、MTOR之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 On the other hand, among the PI3K signal transmission pathway-related proteins which are shown to be inhibited by the combination of GST-π, the drug which inhibits the activity of MTOR is not limited thereto, and for example, it is a giant ring. A rapamycin as a low molecular compound which inhibits the activity of MTOR and inhibits the activity of MTOR (Chang et. al, Trends Pharmacol. Sci. 12: 218-223. 1991), which is a giant ring derived from rapamycin. A low molecular compound of everolimus (Weisblum et. al, Br. Med. Bull. 40: 47-53. 1984), which is an immunosuppressant of a lactone and inhibits the activity of MTOR, is a PI3K tyrosine kinase inhibitor and BEZ235 (Maira et. al, Mol. Cancer Ther. 7(7): 1851-1863.2008), a low molecular compound that inhibits the activity of MTOR, and AZD8055 as a low molecular compound that selectively inhibits the kinase activity of MTOR (Huang et .al, J Biol Chem. Nov 18;286(46):40002-12.2011) PI-103 as a low molecular compound which is a pyridylpyran pyrimidine compound and inhibits the kinase activity of DNA-PK, PI3K and MTOR (Demyanets et al) .2010.Basic Res Cardiol.Mar;106(2):217-31.2011), and niclosamide (Balgi et. Al, PLoS One.Sep 22; 4(9): e7124.2009), PP242 (Bao et al. J. Cell Biol. 210(7): 1153-64.2015), timosaponin AIII (King et. al, PLoS) One.Sep 30;4(9):e7283 2009), KU 0063794 (Garcia-Martinez et al. Biochem. J.421(1):29-42.2009), AZD2014(Guichard et al.Mol.Cancer.Ther.14 (11): 2508-18.2015), temsirolimus (Raymond et al. J. Clin. Oncol. 22: 2336-2347.2004), Palomid 529 (Xue et al. Cancer Res. 68 (22): 9551-7.2008) ), lacquer flavonoids (Suh et. al, Carcinogenesis. Aug; 31 (8): 1424-332010), GDC-0980 (Wallin et al. Mol. Cancer Ther. 10 (12): 2426-36.2011), SF1126 (Garlich Et al. Cancer Res. 68(1): 206-15.2008), CH5132799 (Tanaka et al. Clin Cancer Res. 17(10):3272-81.2011), WYE-354 (Yu et al. Cancer Res. 69 (15) ): 6232-40.2009), Compound 401 (Ballou et al. J. Biol. Chem. 282, 24463.2007), Radus Moss (Gadducci et al.: Gynecol. Endocrinol. 24, 239. 2008), GSK 1059615 (Steven et al. ACS.Med.Chem.Lett.1(1):39-43 2010), PF-04691502 (Yuan et al. Mol. Cancer Ther. 10(11): 2189-99.2011), PP121 (Apsel et al. Nat. Chem. Biol. 4(11): 691-9.2008), OSI-027 (Bhaqwat et al. Mol. Cancer Ther. 10(8): 1394-406.2011), WYE-125132 (Yu et al. Cancer Res. 70 ( 2): 621-31.2010), zotarolimus (Baldo et al. 2008. Curr. Cancer Drug Targets. 8(8): 647-65.2008), WAY-600 (Yu et al. Cancer Res. 69 (15) :6232-40.2009), WYE-687 (Yu et al. Cancer Res. 69(15): 6232-40.2009), PKI-179 (Venkatesan et al. Bioorg. Med. Chem. Lett. 20(19): 5869- 73.2010), PF-05212384 (Akintunde et al. J. Hematol. Oncol. 6: 88.2013), CAY 10626 (Rameh et al. J. Biol. Chem. 274: 8347-8350. 1999), NVP-BGT226 (Chang et al. Clin) .Cancer Res. 17(22): 7116-26.2011), XL-147 derivative 1 (Akintunde et al. J. Hematol. Oncol. 6: 88.2013), XL 388 (Eduardo et al. Mol Cancer Ther. 10 (3) ): 395-403.2011), Torin 1 (Liu et al. J. Med. Chem. 53 (19): 7146-55.2010), RNAi molecule, ribozyme, antisense nucleic acid, DNA/RNA inlay for DNA encoding MTOR Polynucleotides, and the performance of such , MTOR anti-antibody, a dominant negative variant of MTOR like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制IRAK1之活性之藥物，並不限定於此，例如可列舉：為苯并咪唑化合物且特異性地抑制IL-1激酶之活性的作為低分子化合物之介白素1受體相關激酶1/4抑制劑(Bhattacharyya et.al,Am.J.Physiol.Gastrointest.Liver Physiol.293,G429.2007)、針對編碼IRAK1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗IRAK1抗體、IRAK1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which exhibit a synthetic lethality, the drug which inhibits the activity of IRAK1 is not limited to this, and is, for example, a benzimidazole compound and specific. A 1/4 inhibitor of interleukin-1 receptor-associated kinase as a low molecular compound that inhibits the activity of IL-1 kinase (Bhattacharyya et. al, Am. J. Physiol. Gastrointest. Liver Physiol. 293, G429.2007 An RNAi molecule encoding a DNA encoding IRAK1, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and a vector expressing the same, an anti-IRAK1 antibody, a dominant negative variant of IRAK1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑 相關蛋白質之中，作為抑制IRS1之活性之藥物，並不限定於此，例如可列舉：針對編碼IRS1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗IRS1抗體、IRS1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 If it is suppressed together with GST-π, it shows a synthetic lethal PI3K signal transmission path. Among the related proteins, the drug that inhibits the activity of IRS1 is not limited thereto, and examples thereof include an RNAi molecule encoding a DNA encoding IRS1, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and Such vectors, anti-IRS1 antibodies, dominant negative variants of IRS1, and the like are expressed. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制MYD88之活性之藥物，並不限定於此，例如，可列舉作為包含源自抑制同型2聚物化之MYD88之26胺基酸的肽之MyD88抑制肽Pepinh-MYD(Derossi et.al,J.Biol.Chem.,269：10444-50.1994)、特異性地抑制MYD88的作為低分子化合物之TJ-M2010(Li et.al,Transplant Proc.45(5)：1842-5.2013)、針對編碼MYD88之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MYD88抗體、MYD88之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which exhibit a synthetic lethality, the drug which inhibits the activity of MYD88 is not limited to this, and is included as an inclusion-inhibiting isoform 2, for example, if it is suppressed together with GST-π. MyD88 inhibitory peptide Pepinh-MYD (Derossi et. al, J. Biol. Chem., 269: 10444-50.1994) of the polymerized peptide of amino acid MYD88, which specifically inhibits MYD88 as a low molecular compound TJ -M2010 (Li et. al, Transplant Proc. 45(5): 1842-5.2013), RNAi molecule encoding MYD88 DNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, and expression Such vectors, anti-MYD88 antibodies, dominant negative variants of MYD88, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制NFKB1之活性之藥物，並不限定於此，例如可列舉：抑制NF-κB之活化及IκBα之磷酸化之兩活性的作為低分子化合物之BAY 11-7085(Pierce et al.J.Biol.Chem.272：21096-21103.1997)、為誘導細胞凋亡之抗癌劑且抑制NF-κB的作為低分子化合物之心菊內酯(Lyss et al.J.Biol.Chem.273(50)：33508-16.1998)、為HIV整合酶及酪胺酸激酶之抑制劑且特異性地抑制NF-κB之活性的作為低分子化合物之咖啡酸苯乙酯(Sud'ina et al.FEBS Lett.Aug 23；329(1-2)：21-4.1993)、及NFκB活化抑制劑II,JSH-23(Shin et al.FEBS Lett.571：50-54.2004)、QNZ(Tobe et al.Bioorg.Med.Chem.11：3869-3878.2003)、穿心蓮內酯(Yu et al.Planta Med.Dec；69(12)：1075-9.2003)、薑黃素(Asai et al.J.Nutr.131：2932-2935.2001)、阿司匹林 (Kopp et al.Science.265：956-959.1994)、柳氮磺胺吡啶(Liptay et al.Br.J.Pharmacol.128,1361.1999)、楝醯胺(Engelmeier et al.J.Agric.Food Chem.48：1400-1404.2000)、SM 7368(Lee et al.Biochem.Biophys.Res.Commun.336：716-722.2005)、硫化舒林酸(Meade et al.J.Biol.Chem.268：6610-6614.1993)、Trichodion(Erkel et al.FEBS Lett.477,219.2000)、CHS-828(Hovstadius et al.Clin.Cancer Res.8(9)：2843-50.2002)、Z-VRPR-FMK(Hailfinger et al.Proc.Natl.Acad.Sci.U.S.A.106(47)：19946-19951.2009)、水楊酸鈉(Kopp et al.Science.265：956-959.1994)、4-胺基水楊酸(Eberhardt et al.Biochem.Biophys.Res.Commun.200：163-170.1994)、3,4-二羥基肉桂酸乙酯(Nakayama et al.Biosci.Biotechnol.Biochem.60：316-318.1996)、CAY10512(Heynekamp et al.J Med Chem 49 7182-7189 2006)、N-硬脂醯基植物鞘胺醇(Ryu et al.Lipids.45(7)：613-8.2010)、棕櫚酸甲酯(Cai et al.Toxicology.210：197-204.2005)、9-甲基鏈米酮(Ishikawa et al.Bioorg.Med.Chem.Lett.19(6)：1726-8.2009)、洛克米蘭醇(Engelmeier et al.J.Agric.Food Chem.48：1400-1404.2000)、BAY 11-7082(Pierce et al.J.Biol.Chem.272：21096-21103.1997)、針對編碼NFKB1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗NFKB1抗體、NFKB1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to inhibit the synthesis of lethality, the drug which inhibits the activity of NFKB1 is not limited thereto, and examples thereof include inhibition of activation of NF-κB and BAY 11-7085 (Pierce et al. J. Biol. Chem. 272: 21096-21103. 1997), which is a low molecular compound of phosphorylation of IκBα, is an anticancer agent for inducing apoptosis and inhibits NF-κB. As a low molecular compound, heart chrysanthemum (Lyss et al. J. Biol. Chem. 273 (50): 33508-16. 1998), an inhibitor of HIV integrase and tyrosine kinase and specifically inhibits NF-κB Active phenethyl acetonate as a low molecular compound (Sud'ina et al. FEBS Lett. Aug 23; 329(1-2): 21-4.1993), and NFκB activation inhibitor II, JSH-23 (Shin Et al. FEBS Lett. 571:50-54.2004), QNZ (Tobe et al. Bioorg. Med. Chem. 11: 3869-3878.2003), and andrographolide (Yu et al. Planta Med. Dec; 69(12): 1075-9.2003), curcumin (Asai et al. J. Nutr. 131: 2932-2935.2001), aspirin (Kopp et al. Science. 265: 956-959. 1994), sulfasalazine (Liptay et al. Br. J. Pharmacol. 128, 1361.1999), guanamine (Engelmeier et al. J. Agric. Food Chem. 48) :1400-1404.2000), SM 7368 (Lee et al. Biochem. Biophys. Res. Commun. 336: 716-722. 2005), sulindac sulfide (Meade et al. J. Biol. Chem. 268: 6610-6614. 1993), Trichodion (Erkel et al. FEBS Lett. 477, 219.2000), CHS-828 (Hovstadius et al. Clin. Cancer Res. 8(9): 2843-50.2002), Z-VRPR-FMK (Hailfinger et al. Proc. Natl. Acad .Sci. USA 106 (47): 19946-19951. 2009), sodium salicylate (Kopp et al. Science. 265: 956-959. 1994), 4-aminosalicylic acid (Eberhardt et al. Biochem. Biophys. Res. Commun. 200: 163-170.1994), 3,4-dihydroxycinnamate (Nakayama et al. Biosci. Biotechnol. Biochem. 60: 316-318.1996), CAY10512 (Heynekamp et al. J Med Chem 49 7182-7189) 2006), N-stearyl sphingosine sphingosine (Ryu et al. Lipids. 45(7): 613-8.2010), methyl palmitate (Cai et al. Toxicology. 210: 197-204.2005), 9- Methyl chain ketone (Ishikawa et al. Bioorg. Med. Chem. Lett. 19(6): 1726-8.2009), Lokmi Lan alcohol (Engelmeier et al. J. Agric. Food Chem. 48: 1400-1404. 2000), BAY 11-7082 (Pierce et al. J. Biol. Chem. 272: 21096-21103. 1997), RNAi for DNA encoding NFKB1 Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-NFKB1 antibodies, dominant negative variants of NFKB1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制PIK3CG之活性的藥物，並不限定於此，例如可列舉：特異性地抑制HDAC及PI3K之兩活性的作為低分子化合物之CUDC-907(Qian et.al,Clin Cancer Res.18(15)：4104-4113.2012)、特異性地抑制PI3K及mTOR之兩活性的作為低分子化合物之PKI-402(Dehnhardt et.al,J Med Chem.Jan 28；53(2)：798-810.2010)、特異 性地抑制PI3K及mTOR之兩活性的作為低分子化合物之PF-04691502(Yuan et.al,Mol Cancer Ther,10(11),2189-2199.2011)、特異性地抑制PI3K及mTOR之兩活性的作為低分子化合物之NVP-BGT226(Glienke et.al,Tumor Biology,33(3)：757-765.2012)、及IPI-145(INK1197)(Winkler et.al,Chem Biol.2013 Nov 21；20(11)：1364-74.2013)、SAR245409(XL765)(Dai et.al,Endocrinology.Mar；154(3)：1247-592013)、ZSTK474(Toyama et.al,Arthritis Res Ther.12(3)：R92.2010)、VS-5584(SB2343)(Hart et.al,Mol Cancer Ther.2013 Feb；12(2)：151-61.2013)、AS-605240(Camps et.al,Nature medicine,11(9)：936-943.2005)、PIK-90(Van et.al,J Cell Biol.2006 Jul 31；174(3)：437-45.2006)、PF-4989216(Walls et.al,Clin Cancer Res.2014 Feb 1；20(3)：631-43.2014)、TG100-115(Walls et.al,Proc Natl Acad Sci U S A.Dec 26；103(52)：19866-71.2006)、BKM120(Bendell et.al,J.Clin.Oncol.30(3)：282-90.2012)、BEZ235甲苯磺酸鹽(Maira et.al,Mol Cancer Ther 2008；7：1851-1863.2008)、LY294002(Maira et.al,Biochem.Soc.Trans.37(Pt1)：265-72.2009)、PI-103(Raynaud et.al,Molecular Cancer Therapeutics,8(7)：1725-1738.2009)、XL147(Shapiro et.al,Proc 97th Annu Meet AACR,14-18.2007)、AS-252424(Pomel et.al,J Med Chem.Jun 29；49(13)：3857-71.2006)、AS-604850(Camps et.al,Nature medicine,11(9)：936-943.2005)、CAY10505(Tyagi et.al,Can J Physiol Pharmacol.Jul；90(7)：881-5.2012)、CH5132799(Ohwada et.al,Bioorganic & medicinal chemistry letters,21(6)：1767-1772.2011)、BAY 80-6946(Copanlisib)(Patnaik et.al,J Clin Oncol,29,2011)、GDC-0032(Ndubaku et.al,J Med Chem.Jun 13；56(11)：4597-610.2013)、GSK1059615(Knight et.al,ACS Medicinal Chemistry Letters,1(1)：39-43.2010)、CAL- 130(Subramaniam et.al,Cancer Cell.21(4)：459-72.2012)、XL765(Laird et.al,AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.October p.B250 2007)、針對編碼PIK3CG之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗PIK3CG抗體、PIK3CG之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to inhibit the synthesis of lethality, the drug which inhibits the activity of PIK3CG is not limited thereto, and for example, specific inhibition of HDAC and PI3K is exemplified. CUDC-907 (Qian et. al, Clin Cancer Res. 18(15): 4104-4113.2012), which is a low molecular compound, and PKI as a low molecular compound which specifically inhibits both activities of PI3K and mTOR. 402 (Dehnhardt et. al, J Med Chem. Jan 28; 53(2): 798-810.2010), specific PF-04691502 (Yuan et.al, Mol Cancer Ther, 10(11), 2189-2199.2011), a low molecular compound that inhibits both activities of PI3K and mTOR, specifically inhibits both activities of PI3K and mTOR Low molecular compound NVP-BGT226 (Glienke et. al, Tumor Biology, 33(3): 757-765.2012), and IPI-145 (INK1197) (Winkler et. al, Chem Biol. 2013 Nov 21; 20(11) :1364-74.2013), SAR245409 (XL765) (Dai et.al, Endocrinology. Mar; 154(3): 1247-592013), ZSTK474 (Toyama et.al, Arthritis Res Ther. 12(3): R92.2010) VS-5584 (SB2343) (Hart et. al, Mol Cancer Ther. 2013 Feb; 12(2): 151-16.13), AS-605240 (Camps et. al, Nature medicine, 11(9): 936-943.2005 ), PIK-90 (Van et. al, J Cell Biol. 2006 Jul 31; 174(3): 437-45.2006), PF-4989216 (Walls et. al, Clin Cancer Res. 2014 Feb 1; 20(3) : 631-43.2014), TG100-115 (Walls et. al, Proc Natl Acad Sci US A. Dec 26; 103 (52): 19866-71.2006), BKM120 (Bendell et. al, J. Clin. Oncol. 30 ( 3): 282-90.2012), BEZ235 tosylate (Maira et.al, Mol Cancer Ther 2008; 7: 1851-1863.2008), LY294002 (Maira et. al, Bi ochem.Soc.Trans.37 (Pt1): 265-72.2009), PI-103 (Raynaud et. al, Molecular Cancer Therapeutics, 8(7): 1725-1738.2009), XL147 (Shapiro et.al, Proc 97th Annu Meet) AACR, 14-18.2007), AS-252424 (Pomel et. al, J Med Chem. Jun 29; 49(13): 3857-71.2006), AS-604850 (Camps et. al, Nature medicine, 11(9): 936-943.2005), CAY10505 (Tyagi et. al, Can J Physiol Pharmacol. Jul; 90(7): 881-5.2012), CH5132799 (Ohwada et. al, Bioorganic & medicinal chemistry letters, 21(6): 1767-1772.2011 ), BAY 80-6946 (Copanlisib) (Patnaik et. al, J Clin Oncol, 29, 2011), GDC-0032 (Ndubaku et. al, J Med Chem. Jun 13; 56(11): 4597-610.2013), GSK1059615 (Knight et.al, ACS Medicinal Chemistry Letters, 1(1): 39-43.2010), CAL- 130 (Subramaniam et. al, Cancer Cell. 21(4): 459-72.2012), XL765 (Laird et. al, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. October p. B250 2007), for coding An RNAi molecule of a DNA of PIK3CG, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and a vector exhibiting the same, an anti-PIK3CG antibody, a dominant negative variant of PIK3CG, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制RAC1之活性之藥物，並不限定於此，例如，可列舉特異性地抑制Rac GTPase之活性的作為低分子化合物之NSC 23766(Gao et.al,Proc.Natl.Acad.Sci.U.S.A.101：7618-7623.2004)、作為源自RAC1之鳥嘌昤核苷酸交換因子識別/活化位點之肽的W56(Gao et.al,J.Biol.Chem.276 47530.2001)、針對編碼RAC1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗RAC1抗體、RAC1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which exhibit a synthetic lethality, the drug which inhibits the activity of RAC1 is not limited to this, and for example, specific inhibition of Rac GTPase is exemplified. Active as a low molecular compound NSC 23766 (Gao et. al, Proc. Natl. Acad. Sci. USA 101: 7618-7623. 2004), as a guanine nucleotide exchange factor recognition/activation site derived from RAC1 W56 of the peptide (Gao et. al, J. Biol. Chem. 276 47530.2001), RNAi molecule for DNA encoding RAC1, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, and expression of the same Vector, anti-RAC1 antibody, dominant negative variant of RAC1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制AKT3之活性之藥物，並不限定於此，例如可列舉：特異性地抑制Akt1、Akt2及Akt3之活性的作為低分子化合物之MK-2206二鹽酸鹽(Hirai et.al,Mol.Cancer ther.9(7)：1956-67.2010)、特異性地抑制Akt之活性的作為低分子化合物之曲西立濱(Moore et.al,Biochem.Pharmacol.38：4037-4044.1989)、為細胞透過性之喹諾西林化合物且特異性地抑制Akt1、Akt2及Akt3之活性的作為低分子化合物之Akt抑制劑VIII(Barnett et.al,Biochem.J.385：399-408.2005)、源自胺基呋咱之化合物且特異性地抑制Akt1、Akt2及Akt3之活性的作為低分子化合物之GSK 690693(Rhodes et.al,Cancer Res.68(7)：2366-2374.2008)、特異性地抑制Akt1、Akt2及Akt3之活性的作 為低分子化合物之AT7867(Grimshaw et.al,Mol.Cancer Ther.9(5)：1100-10.2010)、針對編碼AKT3之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗AKT3抗體、AKT3之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to be inhibited by the synthesis of the GST-π, the drug which inhibits the activity of AKT3 is not limited thereto, and for example, specific inhibition of Aktl and Akt2 is exemplified. As a low molecular compound, MK-2206 dihydrochloride (Hirai et. al, Mol. Cancer ther. 9(7): 1956-67.2010), which is an activity of Akt3, specifically acts as a low molecular compound for inhibiting the activity of Akt. As a low molecular compound Akt, it is a cell-permeable quinolazine compound and specifically inhibits the activity of Aktl, Akt2 and Akt3. Inhibitor VIII (Barnett et. al, Biochem. J. 385: 399-408. 2005), GSK 690693 (Rhodes) as a low molecular compound that is derived from a compound of amide furan and specifically inhibits the activity of Aktl, Akt2 and Akt3 Et. al, Cancer Res. 68(7): 2366-2374.2008), specifically inhibiting the activity of Aktl, Akt2 and Akt3 AT7867 (Grimshaw et. al, Mol. Cancer Ther. 9(5): 1100-10.2010), a low molecular compound, RNAi molecule, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleus against DNA encoding AKT3 Glyceric acid, and a vector exhibiting the same, an anti-AKT3 antibody, a dominant negative variant of AKT3, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制EIF4B之活性之藥物，並不限定於此，例如可列舉：針對編碼EIF4B之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗EIF4B抗體、EIF4B之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to inhibit the synthesis of lethality, the drug which inhibits the activity of EIF4B is not limited thereto, and examples thereof include RNAi for DNA encoding EIF4B. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-EIF4B antibodies, dominant negative variants of EIF4B, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制EIF4E之活性之藥物，並不限定於此，例如，可列舉特異性地抑制EIF4E/EIF4G之相互作用的作為低分子化合物之4EGI-1(Moerke et.al,Cell.128：257-267.2007)、針對編碼EIF4E之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗EIF4E抗體、EIF4E之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to inhibit the synthesis of lethality, the drug which inhibits the activity of EIF4E is not limited thereto, and for example, specific inhibition of EIF4E/EIF4G is exemplified. Interaction of 4EGI-1 as a low molecular compound (Moerke et.al, Cell. 128: 257-267.2007), RNAi molecule, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleus against DNA encoding EIF4E Glycosylates, and vectors expressing these, anti-EIF4E antibodies, dominant negative variants of EIF4E, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制ILK之活性之藥物，並不限定於此，例如，可列舉細胞透過性之吡唑化合物且特異性地抑制ILK之作為低分子化合物的Cpd 22(Lee et.al,J.Med.Chem.54,6364.2011)、特異性地抑制ILK之激酶活性之作為低分子化合物之QLT0267(Younes et.al,Mol Cancer Ther.Aug；4(8)：1146-56.2005)、針對編碼ILK之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗ILK抗體、ILK之顯性負性變異體等。該等藥物可使用市售 品，或者基於公知之技術而適當製造。 In the case of a PI3K signal-path-transferring protein which exhibits a synthetic lethality, the drug which inhibits the activity of ILK is not limited thereto, and examples thereof include a cell-permeable pyrazole compound. And specifically inhibits ILK as a low molecular compound of Cpd 22 (Lee et. al, J. Med. Chem. 54, 6364.2011), and specifically inhibits the kinase activity of ILK as a low molecular compound QLT0267 (Younes et. Al, Mol Cancer Ther. Aug; 4(8): 1146-56.2005), RNAi molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same for DNA encoding ILK , anti-ILK antibodies, dominant negative variants of ILK, and the like. These drugs can be used commercially Products, or manufactured according to well-known techniques.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制MTCP1之活性之藥物，並不限定於此，例如可列舉：針對編碼MTCP1之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗MTCP1抗體、MTCP1之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal-path-transferring proteins which are shown to inhibit the synthesis of lethality, the drug which inhibits the activity of MTCP1 is not limited thereto, and examples thereof include RNAi for DNA encoding MTCP1. Molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-MTCP1 antibodies, dominant negative variants of MTCP1, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制PIK3CA之活性之藥物，並不限定於此，例如，可列舉特異性地抑制PI3K之作為低分子化合物之HS-173(Lee et.al,Cancer Lett.Jan 1；328(1)：152-9.2013)、特異性地抑制HDAC及PI3K之兩活性的作為低分子化合物之CUDC-907(Qian et.al,Clin Cancer Res.18(15)：4104-4113.2012)、特異性地抑制PI3K及mTOR之兩活性的作為低分子化合物之PKI-402(Dehnhardt et.al,J Med Chem.Jan 28；53(2)：798-810.2010)、特異性地抑制PI3K及mTOR之兩活性之作為低分子化合物的PF-04691502(Yuan et.al,Mol Cancer Ther,10(11),2189-2199.2011)、特異性地抑制PI3K及mTOR之兩活性之作為低分子化合物之NVP-BGT226(Glienke et.al,Tumor Biology,33(3)：757-765.2012)、及BYL719(Furet et.al,Bioorg Med Chem Lett 2013；23：3741-3748.2013)、SAR245409(XL765)(Dai et.al,Endocrinology.Mar；154(3)：1247-592013)、ZSTK474(Toyama et.al,Arthritis Res Ther.12(3)：R92.2010)、VS-5584(SB2343)(Hart et.al,Mol Cancer Ther.2013 Feb；12(2)：151-61.2013)、PIK-75(Zheng et.al,Mol Pharmacol.Oct；80(4)：657-64.2011)、PIK-90(Van et.al,J Cell Biol.2006 Jul 31；174(3)：437-45.2006)、A66(Jamieson et.al,Biochem J.438：53-62.2011)、CNX1351(Nacht et.al,J Med Chem,56(3)：712-721.2013)、PF- 4989216(Walls et.al,Clin Cancer Res.2014 Feb 1；20(3)：631-43.2014)、BKM120(Bendell et.al,J.Clin.Oncol.30(3)：282-90.2012)、BEZ235甲苯磺酸鹽(Maira et.al,Mol Cancer Ther 2008；7：1851-1863.2008)、LY294002(Maira et.al,Biochem.Soc.Trans.37(Pt1)：265-72.2009)、PI-103(Raynaud et.al,Molecular Cancer Therapeutics,8(7)：1725-1738.2009)、XL147(Shapiro et.al,Proc 97th Annu Meet AACR,14-18.2007)、CH5132799(Ohwada et.al,Bioorganic & medicinal chemistry letters,21(6)：1767-1772.2011)、BAY 80-6946(Copanlisib)(Patnaik et.al,J Clin Oncol,29,2011)、GDC-0032(Ndubaku et.al,J Med Chem.Jun 13；56(11)：4597-610.2013)、XL765(Laird et.al,AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.October p.B250 2007)、針對編碼PIK3CA之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗PIK3CA抗體、PIK3CA之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the PI3K signal transmission pathway-related proteins which exhibit a synthetic lethality, the drug which inhibits the activity of PIK3CA is not limited to this, and for example, specific inhibition of PI3K can be cited. Low-molecular compound HS-173 (Lee et. al, Cancer Lett. Jan 1; 328(1): 152-9.2013), CUDC-907 (Qian) as a low molecular compound that specifically inhibits both HDAC and PI3K activities Et. al, Clin Cancer Res. 18(15): 4104-4113.2012), PKI-402 as a low molecular compound which specifically inhibits both PI3K and mTOR activities (Dehnhardt et. al, J Med Chem. Jan 28; 53(2): 798-810.2010), PF-04691502 (Yuan et.al, Mol Cancer Ther, 10(11), 2189-2199.2011), which specifically inhibits the two activities of PI3K and mTOR, as a low molecular compound. NVP-BGT226 as a low molecular compound that inhibits both PI3K and mTOR activities (Glienke et. al, Tumor Biology, 33(3): 757-765.2012), and BYL719 (Furet et. al, Bioorg Med Chem Lett 2013) ; 23: 3741-3748.2013), SAR245409 (XL765) (Dai et. al, Endocrinology. Mar; 154 (3): 1247-592013), ZSTK474 (Toyama et. al, Arthritis Res Ther. 12(3): R92.2010), VS-5584 (SB2343) (Hart et.al, Mol Cancer Ther. 2013 Feb; 12(2): 151-161.2013), PIK-75 (Zheng et. Al, Mol Pharmacol. Oct; 80(4): 657-64.2011), PIK-90 (Van et. al, J Cell Biol. 2006 Jul 31; 174(3): 437-45.2006), A66 (Jamieson et.al) , Biochem J. 438: 53-62.2011), CNX1351 (Nacht et. al, J Med Chem, 56(3): 712-721.2013), PF- 4989216 (Walls et. al, Clin Cancer Res. 2014 Feb 1; 20(3): 631-43.2014), BKM120 (Bendell et. al, J. Clin. Oncol. 30(3): 282-90.2012), BEZ235 toluene Sulfonate (Maira et. al, Mol Cancer Ther 2008; 7: 1851-1863. 2008), LY294002 (Maira et. al, Biochem. Soc. Trans. 37 (Pt1): 265-72. 2009), PI-103 (Raynaud et .al, Molecular Cancer Therapeutics, 8(7): 1725-1738.2009), XL147 (Shapiro et.al, Proc 97th Annu Meet AACR, 14-18.2007), CH5132799 (Ohwada et.al, Bioorganic & medicinal chemistry letters, 21 ( 6): 1767-1772.2011), BAY 80-6946 (Copanlisib) (Patnaik et. al, J Clin Oncol, 29, 2011), GDC-0032 (Ndubaku et. al, J Med Chem. Jun 13; 56(11) : 4597-610.2013), XL765 (Laird et. al, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. October p. B250 2007), RNAi molecules, ribozymes, antisense nucleic acids, DNA encoding PIK3CA, DNA/RNA chimeric polynucleotides, and vectors expressing the same, anti-PIK3CA antibodies, dominant negative variants of PIK3CA, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

若與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關蛋白質之中，作為抑制SRF之活性之藥物，並不限定於此，例如，可列舉細胞透過性之苯并醯胺化合物且特異性地抑制RHO訊號路徑及SRF之活化的作為低分子化合物之CCG-1423(Evelyn et.al,Mol.Cancer Ther.6,2249.2007)、CCG-1423之類似物且特異性地抑制RHO訊號路徑及SRF之活化的作為低分子化合物之CCG-100602(Evelyn,et.al,Bioorg Med Chem Lett 20 665-72.2010)、針對編碼SRF之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸、及表現該等之載體、抗SRF抗體、SRF之顯性負性變異體等。該等藥物可使用市售品，或者基於公知之技術而適當製造。 Among the proteins related to the activity of inhibiting SRF, the drug which inhibits the activity of SRF is not limited to this, and the cell permeable benzopyrene is exemplified as a drug which inhibits the activity of SRF. An amine compound and specifically inhibits activation of the RHO signal pathway and SRF as a low molecular compound CCG-1423 (Evelyn et. al, Mol. Cancer Ther. 6, 2249.2007), an analog of CCG-1423 and specifically inhibits RHO signal pathway and activation of SRF as a low molecular compound CCG-100602 (Evelyn, et. al, Bioorg Med Chem Lett 20 665-72.2010), RNAi molecule for ribonuclease encoding SRF, ribozyme, antisense nucleic acid, DNA /RNA chimeric polynucleotides, and vectors expressing the same, anti-SRF antibodies, dominant negative variants of SRF, and the like. These drugs can be suitably produced using a commercially available product or based on a known technique.

尤其是，作為若與p21等之GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質或抗細胞凋亡相關蛋白質或抑制PI3K訊號傳遞路徑相關蛋白質之產生或活性之藥物，就尤其是特異性高、或副作用之可能性低之方面而言，較佳為針對編碼該蛋白質之DNA的RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等之載體。 In particular, when it is inhibited by GST-π such as p21, it is a drug which exhibits a synthetic lethal cell cycle regulatory protein or an anti-apoptosis-related protein or inhibits the production or activity of a protein related to the PI3K signal transmission pathway. Particularly, in terms of high specificity or low possibility of side effects, it is preferably an RNAi molecule, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and the like for the DNA encoding the protein. Carrier.

該恆常性維持相關蛋白質之抑制與未使針對該蛋白質之抑制劑發揮作用之情形相比，可藉由在細胞中抑制該蛋白質之表現或活性而決定。該蛋白質之表現可藉由已知之任意方法，並無限定，例如可使用利用抗體之免疫沈降法、EIA、ELISA、IRA、IRMA、西方墨點法、免疫組織化學法、免疫細胞化學法、流式細胞儀法、利用編碼該蛋白質之核酸或其特有片段或該核酸之轉錄產物(例如，mRNA)或對剪切產物特異性地進行雜交之核酸的各種雜交法、北方墨點法、南方墨點法、各種PCR法等而評價。 The inhibition of the constant-maintaining related protein can be determined by inhibiting the expression or activity of the protein in the cell as compared with the case where the inhibitor against the protein is not acted upon. The expression of the protein can be any method known by any means, and is not limited, for example, immunoprecipitation using an antibody, EIA, ELISA, IRA, IRMA, Western blotting, immunohistochemistry, immunocytochemistry, flow Cytometry method, various hybridization methods using a nucleic acid encoding the protein or a specific fragment thereof or a transcription product of the nucleic acid (for example, mRNA) or a nucleic acid which specifically hybridizes to a cleavage product, a northern ink dot method, a southern ink Evaluation by point method, various PCR methods, and the like.

又，例如p21之活性可使用p21之已知活性，並無限定，例如可藉由已知之任意方法、例如免疫沈降法、西方墨點法、質量分析法、下拉法、表面電漿子共振(SPR)法等對與週期蛋白-CDK2或週期蛋白-CDK1複合體之結合性等進行分析而評價。 Further, for example, the activity of p21 may be a known activity of p21, and is not limited, for example, by any known method such as immunoprecipitation, Western blotting, mass spectrometry, down-draw, surface plasmon resonance ( The SPR) method and the like are evaluated by analyzing the binding property to the cyclin-CDK2 or the cyclin-CDK1 complex.

於本說明書中使用之情形時，RNAi分子係指帶來RNA干擾之任意分子，並無限定，包含siRNA(small interfering RNA，小干擾RNA)、miRNA(micro RNA，微RNA)、shRNA(short hairpin RNA，短髮夾RNA)、ddRNA(DNA-directed RNA，DNA介導RNA)、piRNA(Piwi-interacting RNA，Piwi交互作用RNA)、rasiRNA(repeat associated siRNA，重複相關siRNA)等雙重鏈RNA及該等之改變體等。該等RNAi分子可使用市售品，或者基於公知之序列資訊、即序列編號1或30、39或108所示之鹼基序列及/或胺基酸序列而設計、製 作。 As used in this specification, the RNAi molecule refers to any molecule that causes RNA interference, and is not limited, and includes siRNA (small interfering RNA), miRNA (micro RNA, microRNA), and shRNA (short hairpin). Double-stranded RNA such as RNA, short hairpin RNA), ddRNA (DNA-directed RNA, DNA-mediated RNA), piRNA (Piwi-interacting RNA, Piwi interaction RNA), rasiRNA (repeat associated siRNA), and Wait for the body to change. These RNAi molecules can be designed and manufactured using commercially available products or based on known sequence information, that is, base sequences and/or amino acid sequences represented by SEQ ID NO: 1 or 30, 39 or 108. Work.

又，於本說明書中使用之情形時，反義核酸包括RNA、DNA、PNA、或該等之複合物。 Further, in the case of use in the present specification, an antisense nucleic acid includes RNA, DNA, PNA, or a complex thereof.

於本說明書中使用之情形時，DNA/RNA嵌合聚核苷酸並無限定，例如包括日本專利特開2003-219893中所記載之包含抑制標靶基因之表現的DNA與RNA之雙鏈聚核苷酸。 In the case of use in the present specification, the DNA/RNA chimeric polynucleotide is not limited, and includes, for example, a double-stranded DNA comprising DNA and RNA which inhibits the expression of a target gene as described in Japanese Patent Laid-Open No. 2003-219893. Nucleotide.

所謂抑制GST-π之藥物及抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物，可包含於單一制劑中，亦可分別包含於2個以上之製劑中。於後者之情形時，各製劑可同時投予，亦可隔開時間而間隔投予。於隔開時間而間隔投予之情形時，可將包含抑制GST-π之藥物之製劑在投予包含抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物製劑之前進行投予，亦可於其後投予。 The drug which inhibits GST-π and the drug which inhibits the synthesis of lethality by the GST-π together with the GST-π can be contained in a single preparation, or may be contained in two or more. In the preparation. In the latter case, the formulations may be administered simultaneously or at intervals of time. When the administration is carried out at intervals of time, the preparation containing the drug for inhibiting GST-π can be administered with a protein containing inhibition to inhibit the synthesis of lethality if it is inhibited together with GST-π. The pharmaceutical preparation is administered prior to administration and may be administered thereafter.

又，於本發明之細胞死亡誘導劑及細胞增殖抑制劑中，上述抑制恆常性維持相關蛋白質之藥物可為1種，亦可為2種以上。例如作為本發明之細胞死亡誘導劑及細胞增殖抑制劑中所含之抑制恆常性維持相關蛋白質的藥物，可使用2種以上之抑制細胞週期相關蛋白質之藥劑，亦可使用2種以上之抑制抗細胞凋亡相關蛋白質之藥劑，亦可使用1種以上之抑制細胞週期相關蛋白質之藥劑及1種以上抑制抗細胞凋亡相關蛋白質的藥劑。 Further, in the cell death inducing agent and the cell proliferation inhibitor of the present invention, the drug for inhibiting the maintenance of the related protein may be one type or two or more types. For example, as a drug for inhibiting the maintenance of a constant-maintaining protein contained in the cell death inducing agent and the cell proliferation inhibitor of the present invention, two or more kinds of agents for inhibiting cell cycle-related proteins may be used, and two or more kinds of inhibition may be used. As the agent for preventing apoptosis-related proteins, one or more agents that inhibit cell cycle-related proteins and one or more agents that inhibit anti-apoptosis-related proteins may be used.

且說，ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、 EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF係若與GST-π一併被抑制則對於癌細胞顯示出合成致死性之恆常性維持相關蛋白質。因此，該抑制蛋白質之藥物係增強因抑制GST-π之藥物所引起之細胞死亡誘導及/或細胞增殖抑制之劑或組合物(以下亦稱為「細胞死亡誘導增強劑」、「細胞增殖抑制增強劑」、「細胞死亡誘導增強用組合物」或「細胞增殖抑制增強用組合物」)作為有效成分。換言之，藉由投予有效量之抑制該蛋白質之藥物，可增強因投予抑制GST-π之藥物引起之細胞死亡之誘導及/或細胞增殖之抑制。 And said, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1 BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, When EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF are inhibited together with GST-π, the expression of synthetic lethality is maintained for cancer cells to maintain related proteins. Therefore, the protein-inhibiting drug enhances cell death induction and/or cell proliferation inhibition by a drug that inhibits GST-π (hereinafter also referred to as "cell death-inducing enhancer", "cell proliferation inhibition" An enhancer, a "cell death-inducing enhancing composition" or a "cell proliferation inhibiting-enhancing composition" is used as an active ingredient. In other words, by administering an effective amount of a drug for inhibiting the protein, induction of cell death and/or inhibition of cell proliferation by administration of a drug inhibiting GST-π can be enhanced.

關於本發明之劑或組合物中之有效成分之調配量，於投予劑或組合物之情形時，可為誘導細胞凋亡之細胞死亡及/或抑制細胞增殖的量。又，較佳為不產生超過投予所產生之利益之不良影響之量。該量為公知，可藉由使用培養細胞等之活體外試驗或小鼠、大鼠、狗或豬等模型動物之試驗而適當決定，此種試驗法係從業者所熟知。細胞凋亡之誘導可藉由各種已知方法、例如DNA片段化、膜聯蛋白V之對細胞膜之結合、線粒體膜電位之變化、半胱天冬酶之活化等之細胞凋亡特有之現象之檢測或TUNEL染色等進行評價。又，細胞增殖之抑制可藉由各種已知方法、例如經時性之活細胞數之計數、腫瘤之尺寸、體積或重量之測定、DNA合成量之測定、WST-1法、BrdU(溴去氧尿苷)法、3H胸苷取入法等進行評價。活性成分之調配量可根據劑或組合物之投藥態樣而變化。例如，於1次投予使用複數個單位之組合物之情形，調配至組合物1單位中之有效成分之量可設為1次投予所需之有效成分之量之複數分之一。該調配量之調整可由從業者適當進行。 The amount of the active ingredient in the agent or composition of the present invention may be an amount which induces apoptosis and/or inhibits cell proliferation in the case of the administration agent or composition. Further, it is preferred that the amount that does not adversely affect the benefit generated by the administration is not generated. This amount is well known and can be appropriately determined by an in vitro test using cultured cells or the like, or a test of a model animal such as a mouse, a rat, a dog or a pig, and such a test method is well known to the practitioner. The induction of apoptosis can be caused by various known methods, such as DNA fragmentation, binding of annexin V to cell membranes, changes in mitochondrial membrane potential, activation of caspase, and the like. Evaluation was performed by detection or TUNEL staining or the like. Further, the inhibition of cell proliferation can be carried out by various known methods, such as counting the number of viable cells over time, measuring the size, volume or weight of the tumor, measuring the amount of DNA synthesis, WST-1 method, BrdU (bromo removal). The oxyuridine method, the 3H thymidine incorporation method, and the like were evaluated. The amount of the active ingredient to be formulated may vary depending on the dosage form of the agent or composition. For example, in the case where a composition of a plurality of units is administered once, the amount of the active ingredient to be formulated into one unit of the composition may be set to be a plural of the amount of the active ingredient required for one administration. The adjustment of the adjustment amount can be appropriately performed by the practitioner.

又，藉由調配抑制GST-π之藥物及抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物作為有效成分，可製造細胞死亡誘導劑、細胞增殖抑制劑、細胞死亡誘導組合物或細胞 增殖抑制組合物。 In addition, by modulating a drug that inhibits GST-π and inhibiting a drug that exhibits a synthetic lethality-maintaining related protein when it is inhibited together with GST-π, a cell death inducing agent, cell proliferation can be produced. Inhibitor, cell death inducing composition or cell Proliferation inhibiting composition.

進而，可提供用於細胞死亡誘導或細胞增殖抑制的抑制GST-π之藥物與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物之組合。進而，可提供包括投予有效量之抑制GST-π之藥物及抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質之藥物的細胞死亡之誘導方法或細胞增殖之抑制方法。 Further, it is possible to provide a combination of a drug for inhibiting GST-π for cell death induction or cell proliferation inhibition and a drug for inhibiting the expression of a synthetic lethality-maintaining related protein if it is inhibited together with GST-π. Further, a method or a cell for inducing cell death including administration of an effective amount of a drug for inhibiting GST-π and a drug for inhibiting a gene which exhibits a synthetic lethality to maintain a related protein when inhibited together with GST-π can be provided. The method of inhibition of proliferation.

再者，上述細胞凋亡等細胞死亡誘導或細胞增殖抑制方法可為活體外之方法，亦可為活體內之方法。又，關於該方法中之藥物，如上所述，藥物之有效量可為於投予之細胞中誘導細胞死亡或抑制細胞增殖之量。又，較佳為不產生超過投予所產生之利益之不良影響之量。該量為公知，或可藉由使用培養細胞等之活體外試驗等而適當決定，此種試驗法係從業者所熟知。細胞死亡之誘導或細胞增殖之抑制可藉由包含上述者之各種已知方法進行評價。關於上述有效量，於將藥物投予至特定癌細胞集團之情形時，亦可並非對同一細胞集團之所有細胞均帶來細胞死亡或增殖抑制。例如，上述有效量可為該細胞集團中之細胞之1%以上、2%以上、3%以上、4%以上、5%以上、6%以上、8%以上、10%以上、12%以上、15%以上、20%以上、進而25%以上等帶來細胞凋亡或增殖抑制之量。 Further, the cell death-inducing or cell proliferation-inhibiting method such as apoptosis may be an in vitro method or an in vivo method. Further, as for the drug in the method, as described above, the effective amount of the drug may be an amount which induces cell death or inhibits cell proliferation in the administered cells. Further, it is preferred that the amount that does not adversely affect the benefit generated by the administration is not generated. This amount is known or can be appropriately determined by an in vitro test using cultured cells or the like, and such a test method is well known to the practitioner. Induction of cell death or inhibition of cell proliferation can be evaluated by various known methods including the above. With regard to the above-mentioned effective amount, when the drug is administered to a specific cancer cell group, it is not possible to cause cell death or proliferation inhibition to all cells of the same cell group. For example, the effective amount may be 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 8% or more, 10% or more, or 12% or more of the cells in the cell group. The amount of apoptosis or proliferation inhibition is caused by 15% or more, 20% or more, and further 25% or more.

本發明之細胞死亡誘導劑或細胞增殖抑制劑於癌細胞中亦可有效地誘導細胞死亡，或可抑制細胞增殖，故而作為針對起因於細胞之增殖異常之疾病的醫藥組合物之成分較有效。又，藉由調配抑制GST-π之藥物及抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物作為有效成分，則可製造針對起因於細胞之增殖異常之疾病的醫藥組合物。進而，包括將所製造之醫藥組合物之有效量投予至需要其之對象，而可處置、治療起因於細胞之增殖異常之 疾病。 The cell death inducing agent or the cell proliferation inhibitor of the present invention can also effectively induce cell death in cancer cells or inhibit cell proliferation, and thus is effective as a component of a pharmaceutical composition for a disease caused by abnormal proliferation of cells. In addition, by blending a drug that inhibits GST-π and suppressing a drug that exhibits a synthetic lethality to maintain a related protein as an active ingredient when it is inhibited together with GST-π, it is possible to produce a proliferation effect on cells. A pharmaceutical composition for an abnormal disease. Further, it comprises administering an effective amount of the produced pharmaceutical composition to a subject in need thereof, and treating and treating the abnormality of the cell caused by the abnormality of the cell disease.

該醫藥組合物對處置起因於細胞之增殖異常之疾病尤其處置藉由表現變異型KRAS而對細胞死亡或細胞增殖具有異常之疾病有效。 This pharmaceutical composition is effective for treating a disease caused by abnormal proliferation of cells, in particular, by treating a variant KRAS and having an abnormality in cell death or cell proliferation.

作為起因於表現變異型KRAS之細胞之疾病，並無限定，例如包括良性或惡性腫瘤(亦稱為癌、惡性新生物)、增生症、瘢痕瘤、庫欣氏症候群、原發性醛固酮症、紅板症、真性多血症、白板症、增生瘢痕、扁平苔癬及色素小斑症等。 The disease caused by the cell expressing the variant KRAS is not limited, and includes, for example, benign or malignant tumors (also called cancer, malignant neoplasms), hyperplasia, keloid, Cushing's syndrome, primary aldosteronism, Red plate disease, true plethora, white matter, hypertrophic scar, lichen planus and pigmentation plaque.

作為本發明中之癌，例如可列舉：癌、高度表現GST-π之癌、起因於表現變異型KRAS之細胞的癌(亦有簡稱為KRAS癌之情形)等，多數情形時KRAS癌包括在高度表現GST-π之癌中。作為該等，並無限定，例如可列舉：纖維肉瘤、惡性纖維性組織球瘤、脂肪肉瘤、橫紋肌肉瘤、平滑肌肉瘤、血管肉瘤、卡波西氏肉瘤、淋巴管肉瘤、滑膜肉瘤、軟骨肉瘤、骨肉瘤等肉瘤，腦腫瘤、頭頸部癌、乳癌、肺癌、食道癌、胃癌、十二指腸癌、闌尾癌、大腸癌、直腸癌、肝癌、胰腺癌、膽嚢癌、膽管癌、肛門癌、腎癌、尿道癌、膀胱癌、攝護腺癌、陰莖癌、睾丸癌、子宮癌、卵巢癌、外陰癌、陰道癌、皮膚癌等癌瘤、進而白血病或惡性淋巴瘤等。再者，於本發明中，「癌」包括上皮性惡性腫瘤及非上皮性惡性腫瘤。本發明中之癌可存在於身體之任意部位、例如腦、頭頸部、胸部、四肢、肺、心臟、胸腺、食道、胃、小腸(十二指腸、空腸、回腸)、大腸(結腸、盲腸、闌尾、直腸)、肝臟、胰臟、膽嚢、肛門、腎、尿道、膀胱、攝護腺、陰莖、睾丸、子宮、卵巢、外陰、陰道、皮膚、橫紋肌、平滑肌、滑膜、軟骨、骨、甲狀腺、副腎、腹膜、腸間膜、骨髓、血液、血管系統、淋巴節等淋巴系統、淋巴液等。 Examples of the cancer in the present invention include cancer, cancer which highly expresses GST-π, cancer caused by cells exhibiting variant KRAS (also referred to as KRAS cancer), and KRAS cancer is included in most cases. Highly expressed in GST-π cancer. As such, it is not limited, and examples thereof include fibrosarcoma, malignant fibrous tissue tumor, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, chondrosarcoma. , osteosarcoma and other sarcoma, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, duodenal cancer, appendix cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, biliary cancer, cholangiocarcinoma, anal cancer, kidney Cancer, urinary tract cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, skin cancer and other cancers, and thus leukemia or malignant lymphoma. Furthermore, in the present invention, "cancer" includes epithelial malignant tumors and non-epithelial malignant tumors. The cancer of the present invention may be present in any part of the body, such as the brain, head and neck, chest, limbs, lung, heart, thymus, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (colon, cecum, appendix, Rectum), liver, pancreas, biliary fistula, anus, kidney, urethra, bladder, prostate, penis, testis, uterus, ovary, vulva, vagina, skin, striated muscle, smooth muscle, synovium, cartilage, bone, thyroid, Paranephrosis, peritoneum, intestinal membrane, bone marrow, blood, vascular system, lymphatic system and other lymphatic system, lymph fluid, etc.

作為醫藥組合物，除了抑制GST-π之藥物及抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物以外，亦 可併用其他有效成分。此處，所謂併用，包含例如將其他有效成分以個別製劑之形式進行投予，及將其他有效成分以與至少1種其他藥劑之合劑之形式進行投予等。作為以個別製劑之形式進行投予之情形，可將包含其他有效成分之製劑於投予其他製劑之前、與投予其他製劑之同時，或投予其他製劑之後進行投予。 As a pharmaceutical composition, in addition to a drug that inhibits GST-π and a drug that inhibits the synthesis of lethality and maintains a related protein if it is inhibited together with GST-π, Other active ingredients can be used in combination. Here, the combination includes, for example, administration of other active ingredients in the form of individual preparations, and administration of other active ingredients in the form of a mixture with at least one other medicine. In the case of administration as an individual preparation, the preparation containing the other active ingredient may be administered before administration of other preparations, administration of other preparations, or administration of other preparations.

作為其他有效成分，可列舉對成為對象之疾病之處置有效者。例如於所處置之疾病為癌之情形時，可併用抗癌劑。作為抗癌劑之例，例如可列舉：異環磷醯胺、鹽酸尼莫司汀、環磷醯胺、氮烯唑胺、美法侖、雷莫司汀等烷基化劑，鹽酸吉西他濱、依諾他濱、阿糖胞苷十八烷基磷酸鹽、阿糖胞苷製劑、喃氟啶-尿嘧啶、喃氟啶-吉莫斯特-奧替拉西鉀調配劑(例如，TS-1)、去氧氟尿苷、羥基脲、氟尿嘧啶、甲胺喋呤、巰基嘌呤等代謝拮抗劑，鹽酸艾達黴素、鹽酸表柔比星、鹽酸道諾黴素、檸檬酸道諾黴素、鹽酸多柔比星、鹽酸吡柔比星、鹽酸博萊黴素、硫酸培洛黴素、鹽酸米托蒽醌、絲裂黴素C等抗腫瘤性抗生物質，依託泊苷、鹽酸伊立替康、酒石酸長春瑞濱、歐洲紫杉醇水合物、紫杉醇、硫酸長春新鹼、硫酸長春地辛、硫酸長春花鹼等生物鹼，阿那曲唑、檸檬酸他莫昔芬、檸檬酸托瑞米芬、比卡魯胺、氟他胺、磷酸雌莫司汀等激素療法劑，卡鉑、順鉑(CDDP)、奈達鉑等鉑錯合物，散利醯胺、奈巴司他、貝凡單抗等血管新生抑制劑、L-天冬醯胺酶等。 Examples of other active ingredients include those effective for the treatment of the target disease. For example, when the disease to be treated is cancer, an anticancer agent can be used in combination. Examples of the anticancer agent include, for example, an alkylating agent such as ifosfamide, nitustine hydrochloride, cyclophosphamide, carbazolamide, melphalan, ramustine, gemcitabine hydrochloride, Enesitabine, cytarabine octadecyl phosphate, cytarabine preparation, fluridine-uracil, fluridine-gimoster-oteracilide potassium formulation (eg, TS- 1), metabolic inhibitors such as deoxyfluorouridine, hydroxyurea, fluorouracil, methotrexate, guanidinium, edamycin hydrochloride, epirubicin hydrochloride, daunorubicin hydrochloride, daunorubicin , anti-tumor antibiotics such as doxorubicin hydrochloride, pirarubicin hydrochloride, bleomycin hydrochloride, pedicillin sulfate, mitoxantrone hydrochloride, mitomycin C, etoposide, irinotene hydrochloride Kang, vinorelbine tartrate, European paclitaxel hydrate, paclitaxel, vincristine sulfate, vindesine sulfate, vinblastine sulfate, alkaloids, anastrozole, tamoxifen citrate, toremifene citrate, Hormone therapeutics such as bicalutamide, flutamide, estramustine phosphate, carboplatin, cisplatin (CDDP), nedaplatin, etc. Platinum complexes, angiogenesis inhibitors such as linoleamide, napastat, bevacizumab, and L-aspartate.

於本說明書中所記載之本發明之各種劑或組合物、處置方法等之活性成分為核酸、例如RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸等之情形時，該等可以裸核酸之形式直接利用，亦可擔載於各種載體上。作為載體，可利用質體載體、噬菌體載體、噬菌體醯胺載體、黏接質體載體、病毒載體等公知之任意者。載體較佳為至少包含增強擔載之核酸之表現的啟動子，於該情形時，較佳為該核酸與 該啟動子以可作動之方式連結。所謂核酸與啟動子以可作動之方式連結，意指以藉由啟動子之作用而使編碼該核酸之蛋白質適當產生之方式配置該核酸及啟動子。載體可於宿主細胞內複製，又，基因之轉錄可於宿主細胞之核外進行，亦可於核內進行。於後者之情形時，核酸可取入至宿主細胞之基因組中。 When the active ingredients of the various agents, compositions, and methods of treatment of the present invention described in the present specification are nucleic acids, for example, RNAi molecules, ribozymes, antisense nucleic acids, DNA/RNA chimeric polynucleotides, and the like, These may be used directly in the form of naked nucleic acids or may be carried on various carriers. As the carrier, any known ones such as a plastid vector, a phage vector, a phage guanamine carrier, an adhesive plastid vector, and a viral vector can be used. Preferably, the vector comprises at least a promoter that enhances the expression of the supported nucleic acid, in which case the nucleic acid is preferably The promoter is linked in an actuatable manner. The nucleic acid and the promoter are operably linked, and the nucleic acid and the promoter are arranged such that the protein encoding the nucleic acid is appropriately produced by the action of the promoter. The vector can be replicated in a host cell, and transcription of the gene can be carried out outside the nucleus of the host cell or in the nucleus. In the latter case, the nucleic acid can be taken into the genome of the host cell.

又，有效成分亦可擔載於各種非病毒性脂質或蛋白質載體上。作為該載體，並無限定，例如可列舉：膽固醇、脂質體、抗體質子、環糊精奈米粒子、融合肽、適體、生物降解性聚乳酸共聚物、聚合物等，可提高對細胞內之取入效率(例如參照Pirollo and Chang,Cancer Res.2008；68(5)：1247-50等)。尤其是，陽離子性脂質體或聚合物(例如聚伸乙基亞胺等)較有用。作為該載體有用之聚合物之進一步之例，例如可列舉US 2008/0207553、US 2008/0312174等中所記載者等。 Further, the active ingredient may be carried on various non-viral lipid or protein carriers. The carrier is not limited, and examples thereof include cholesterol, liposome, antibody proton, cyclodextrin nanoparticles, fusion peptide, aptamer, biodegradable polylactic acid copolymer, and polymer, which can be improved in cells. Intake efficiency (see, for example, Pirollo and Chang, Cancer Res. 2008; 68(5): 1247-50, etc.). In particular, cationic liposomes or polymers (e.g., polyethylenimine, etc.) are useful. Further examples of the polymer which is useful as the carrier include, for example, those described in US 2008/0207553, US 2008/0312174, and the like.

於本說明書中所記載之本發明之各種醫藥組合物中，只要不妨礙活性成分之效果，可將活性成分與其他任意成分組合。作為此種任意成分，例如可列舉：其他化學治療劑、藥理學上容許之載體、賦形劑、稀釋劑等。又，可根據投予路徑或藥物釋放形式等，而將上述組合物由適當之材料、例如腸溶性之包衣或時限崩解性之材料所被覆，又，亦可取入至適當之藥物釋放系統中。 The various pharmaceutical compositions of the present invention described in the present specification may be combined with other optional components as long as they do not interfere with the effects of the active ingredients. Examples of such an optional component include other chemotherapeutic agents, pharmacologically acceptable carriers, excipients, and diluents. Further, the above composition may be coated with a suitable material such as an enteric coating or a time-disintegrating material depending on the administration route or the form of drug release, etc., or may be taken into an appropriate drug delivery system. in.

本說明書中所記載之本發明之各種劑及組合物(包含各種醫藥組合物)可採用包含經口及非經口兩者在內之各種路徑，例如可無限定地適當採用經口、靜脈內、肌肉內、皮下、局部、腫瘤內、直腸、動脈內、門靜脈內、心室內、經黏膜、經皮、鼻內、腹腔內、肺內及子宮內等之路徑投予，亦可製成適於各投予路徑之劑型的製劑。該劑型及製劑方法可適當採用任意之公知者(例如參照標準藥劑學，渡邊喜照等人編纂，南江堂，2003年等)。 The various agents and compositions of the present invention (including various pharmaceutical compositions) described in the present specification may employ various routes including both oral and parenteral, and for example, oral or intravenous administration may be suitably employed without limitation. , intramuscular, subcutaneous, local, intratumoral, rectal, intraarterial, portal vein, intraventricular, transmucosal, percutaneous, intranasal, intraperitoneal, intrapulmonary, and intrauterine, etc. A formulation of the dosage form for each administration route. The dosage form and the preparation method can be appropriately selected from any known person (for example, refer to standard pharmacy, edited by Watanabe et al., Nanjiang Hall, 2003, etc.).

例如，作為適於經口投予之劑型，並無限定，可列舉：散劑、 顆粒劑、錠劑、膠囊劑、液劑、懸浮劑、乳劑、凝膠劑、糖漿劑等，又，作為適於非經口投予之劑型，可列舉：溶液性注射劑、懸浮性注射劑、乳濁性注射劑、用時製備型注射劑等注射劑。非經口投予用製劑可為水性或非水性之等張性無菌溶液或懸浮液之形態。 For example, the dosage form suitable for oral administration is not limited, and examples thereof include a powder, A granule, a lozenge, a capsule, a liquid, a suspension, an emulsion, a gel, a syrup, etc., and as a dosage form suitable for parenteral administration, a solution injection, a suspension injection, and a milk are mentioned. An injection such as a turbid injection or a preparation for injection. The preparation for parenteral administration can be in the form of an aqueous or nonaqueous isotonic sterile solution or suspension.

本說明書中所記載之本發明之各種劑或組合物(包括各種醫藥組合物)可對特定之組織或細胞進行尋靶。尋靶可藉由已知之任意方法而達成。於意欲對癌之傳遞之情形時，並無限定，例如可使用藉由將製劑製成對EPR(enhanced permeability and retention)效果之表現較佳之直徑50~200μm、尤其是75~150μm等尺寸而進行之被動標靶，或者利用CD19、HER2、轉鐵蛋白受體、葉酸受體、VIP受體、EGFR(Torchilin,AAPS J.2007；9(2)：E128-47)、RAAG10(日本專利特表2005-532050)、PIPA(日本專利特表2006-506071)、KID3(日本專利特表2007-529197)等配位子或具有RGD結構或NGR結構之肽、F3、LyP-1(Ruoslahti et al.,J Cell Biol.2010；188(6)：759-68)等作為尋靶劑之主動標靶等方法。又，亦已知視黃醇類或其衍生物作為對癌細胞之尋靶劑有用(WO 2008/120815)，因此亦可利用包含視黃醇類作為尋靶劑之載體。該載體除了上述文獻外，亦記載於WO 2009/036368、WO 2010/014117、WO 2012/170952等。 The various agents or compositions of the invention (including various pharmaceutical compositions) described in this specification can be targeted to a particular tissue or cell. Targeting can be achieved by any method known. It is not limited as long as it is intended to transmit cancer, and for example, it can be used by making the preparation into a size having a diameter of 50 to 200 μm, particularly 75 to 150 μm, which is preferable for an EPR (enhanced permeability and retention) effect. Passive targets, or use CD19, HER2, transferrin receptor, folate receptor, VIP receptor, EGFR (Torchilin, AAPS J.2007; 9(2): E128-47), RAAG10 (Japanese Patent Special Table) 2005-532050), PIPA (Japanese Patent Special Table 2006-506071), KID3 (Japanese Patent Special Table 2007-529197), etc., or a peptide having an RGD structure or an NGR structure, F3, LyP-1 (Ruoslahti et al. , J Cell Biol. 2010; 188 (6): 759-68) and the like as an active target of a homing agent. Further, it is also known that retinol or a derivative thereof is useful as a targeting agent for cancer cells (WO 2008/120815), and therefore a carrier containing retinol as a targeting agent can also be used. In addition to the above documents, the vector is also described in WO 2009/036368, WO 2010/014117, WO 2012/170952 and the like.

本說明書中所記載之本發明之各種劑或組合物(包括各種醫藥組合物)可以任一形態供給，就保存穩定性之觀點而言，可以可用時製備之形態、例如醫療之現場或其附近，能夠由醫師及/或藥劑師、護士、或其他醫務輔助人員等進行製備之形態提供。該形態於本發明之劑或組合物包含脂質或蛋白質、核酸等難以穩定保存之成分時尤其有用。於該情形時，本發明之劑或組合物係以該等中包含所需之構成要素之至少一個的1個或2個以上之容器而提供，於使用之前例如24小時前以內、較佳為3小時前以內、並且更佳為剛使用之前進行製備。於 製備時，於製備之場所，可適當使用通常可獲取之試劑、溶劑、調劑器具等。 The various agents or compositions (including various pharmaceutical compositions) of the present invention described in the present specification may be supplied in any form, and may be prepared in a form usable when it is used, for example, at or near a medical site from the viewpoint of storage stability. It can be provided in the form of preparation by a physician and/or a pharmacist, a nurse, or other medical support personnel. This form is particularly useful when the agent or composition of the present invention contains a component such as a lipid, a protein, or a nucleic acid which is difficult to stably store. In this case, the agent or composition of the present invention is provided in one or two or more containers containing at least one of the required constituent elements, and is used, for example, within 24 hours before use, preferably It is prepared within 3 hours before, and more preferably just before use. to At the time of preparation, generally available reagents, solvents, dispensing devices, and the like can be suitably used at the place of preparation.

因此，本發明亦關於一種將本發明之各種劑或組合物可含有之活性成分以包含單獨或組合包含之1個或2個以上之容器的組合物之製備套組、以及此種套組之形態提供之各種劑或組合物之必要構成要素。本發明之套組除上述以外，亦可包含記載有本發明之各種劑或組合物之製備方法或投予方法等之指示，例如說明書或CD、DVD等電子記錄媒體等。又，本發明之套組可包含用以完成本發明之各種劑或組合物之全部構成要素，但亦可並未包含全部構成要素亦可。因此，本發明之套組可包含於醫療現場或實驗設施等處通常可獲取之試劑或溶劑、例如無菌水或生理食鹽水、葡萄糖溶液等。 Accordingly, the present invention is also directed to a kit for preparing a composition comprising the active ingredients of the various agents or compositions of the present invention, comprising a composition comprising one or more containers, alone or in combination, and such kits The necessary constituent elements of the various agents or compositions provided by the form. The kit of the present invention may include, in addition to the above, instructions for preparing a preparation method, a administration method, and the like of various agents or compositions of the present invention, for example, an instruction manual, an electronic recording medium such as a CD or a DVD, or the like. Further, the kit of the present invention may contain all of the constituent elements of the various agents or compositions of the present invention, but may not include all of the constituent elements. Thus, the kit of the present invention may comprise reagents or solvents commonly available at a medical site or laboratory facility, such as sterile water or physiological saline, dextrose solution, and the like.

本說明書中所記載之本發明之各種處置方法之有效量係例如降低疾病之症狀、或延遲或停止疾病之進行之量，較佳為抑制疾病或治癒疾病之量。又，較佳為不產生超過投予所產生之利益的不良影響之量。該量可根據使用培養細胞等之活體外試驗或小鼠、大鼠、狗或豬等之模型動物之試驗而適當決定，此種試驗法係從業者所熟知。又，本發明之處置方法使用之藥物之用量係從業者公知，或可利用上述試驗等而適當決定。 The effective amount of each of the treatment methods of the present invention described in the present specification is, for example, an amount which reduces the symptoms of the disease or delays or stops the progress of the disease, and is preferably an amount which inhibits the disease or cures the disease. Further, it is preferable that the amount which does not cause an adverse effect exceeding the benefit of the administration is generated. The amount can be appropriately determined depending on an in vitro test using cultured cells or the like, or a test for a model animal such as a mouse, a rat, a dog or a pig, and such a test method is well known to the practitioner. Further, the amount of the drug to be used in the treatment method of the present invention is known to the practitioner or may be appropriately determined by the above test or the like.

於本說明書中所記載之本發明之處置方法中，所投予之活性成分之具體用量可考慮需要處置之對象相關之各種條件、例如症狀之嚴重度、對象之一般健康狀態、年齡、體重、對象之性別、食物、投予之時期及頻度、併用之醫藥、對治療之反應性、劑型、及針對治療之依從性等而決定。 In the treatment method of the present invention described in the present specification, the specific amount of the active ingredient to be administered may take into consideration various conditions related to the subject to be treated, such as the severity of the symptoms, the general health state of the subject, age, body weight, The sex of the subject, the food, the period and frequency of the administration, the combination of the medicine, the response to the treatment, the dosage form, and the compliance with the treatment are determined.

作為投予路徑，包含包括經口及非經口兩者在內之各種路徑、例如經口、靜脈內、肌肉內、皮下、局部、腫瘤內、直腸、動脈內、門靜脈內、心室內、經黏膜、經皮、鼻內、腹腔內、肺內及子宮內等 路徑。 As a route of administration, it includes various routes including oral and non-oral, such as oral, intravenous, intramuscular, subcutaneous, topical, intratumoral, rectal, intraarterial, portal vein, intraventricular, and Mucosa, percutaneous, intranasal, intraperitoneal, intrapulmonary and intrauterine path.

投予頻度根據所使用之劑或組合物之性狀、或包括上述在內之對象之條件而異，例如可為1天多次(即，1天2、3、4次或5次以上)、1天1次、每數天(即，每2、3、4、5、6、7天等)、每1週、每數週(即，每2、3、4週等)。 The frequency of administration varies depending on the properties of the agent or composition to be used, or the conditions of the subject including the above, and may be, for example, one or more times per day (ie, one day, two, three, four or more times). Once a day, every few days (ie, every 2, 3, 4, 5, 6, 7 days, etc.), every 1 week, every few weeks (ie, every 2, 3, 4 weeks, etc.).

於本說明書中使用之情形時，用語「對象」意指任意之生物個體，較佳為動物，進而較佳為哺乳動物，進而較佳為人類之個體。於本發明中，對象可為健康，亦可為罹患任何疾病者，於意欲處置特定疾病之情形時，典型而言意指罹患某種疾病，或有罹患風險之對象。 In the context of the present specification, the term "subject" means any biological individual, preferably an animal, and more preferably a mammal, and more preferably an individual of a human. In the present invention, the subject may be healthy or may be suffering from any disease, and when it is intended to treat a particular disease, it typically means a subject suffering from a certain disease or at risk.

又，用語「處置」於本說明書中使用之情形時，包括以疾病之治癒、暫時緩解或預防等為目的之醫學上容許之全部種類之預防及/或治療性之介入。例如，「處置」之用語包括包含疾病進行之延遲或停止、病變之退縮或消失、發病之預防或復發之防止等各種目的之醫學上容許之介入。 Further, the term "disposal" as used in the present specification includes all types of medically acceptable prevention and/or therapeutic intervention for the purpose of curing, temporary relief or prevention of diseases. For example, the term "disposal" includes medically permissible interventions for various purposes including delay or cessation of the disease, withdrawal or disappearance of the lesion, prevention of the onset, or prevention of relapse.

且說，如上所述，ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1、AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2、MYO18A、MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF係若與GST-π一併被抑制則對於癌細胞顯示出合成致死性之蛋白質。因此，可對以針對該等恆常性維持相關蛋白質之抑制作為指標，與抑制GST-π之藥物一併使用的癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑進行篩選。即，該等可抑制恆常性維持相關蛋白質之物質係與抑制GST-π之藥物一併使用之癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之候 補物質。 And, as mentioned above, ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1, AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1 BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, MYO18A, MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA and When the SRF system is inhibited together with GST-π, it exhibits a synthetic lethal protein to cancer cells. Therefore, it is possible to screen for a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell which is used together with a drug which inhibits GST-π as an index for the inhibition of the related protein. That is, the cell death inducing agent and/or the cell proliferation inhibitor of the cancer cell which inhibits the constant maintenance of the related protein and the cancer cell which inhibits the GST-π is used. Substance.

例如作為癌細胞之一例，使受檢物質接觸表現變異型KRAS之細胞，並測定該細胞中之若與GST-π一併被抑制則對於表現變異型KRAS之細胞顯示出合成致死性之上述恆常性維持相關蛋白質之表現量。於與在受檢物質之非存在下所測得之表現量相比，接觸受檢物質時之表現量降低之情形時，可選擇該受檢物質作為上述抑制恆常性維持相關蛋白質之藥物之候補物質。 For example, as an example of a cancer cell, a test substance is brought into contact with a cell expressing a variant KRAS, and if the cell is inhibited together with GST-π, the cell exhibiting a mutant KRAS exhibits the above-mentioned constant lethality. The performance of related proteins is maintained routinely. When the amount of expression when the test substance is contacted is lowered as compared with the amount of expression measured in the absence of the test substance, the test substance may be selected as the drug for inhibiting the constantity-maintaining related protein. Alternative substances.

另一方面，抑制GST-π之藥物係若與抑制若與GST-π一併被抑制則對癌細胞顯示出合成致死性之上述恆常性維持相關蛋白質的藥劑一併進行抑制，則對癌細胞顯示出合成致死性之蛋白質。因此，可對以針對GST-π之抑制作為指標，與上述抑制恆常性維持相關蛋白質之藥劑一併使用的癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑進行篩選。即，可抑制GST-π之物質成為與上述抑制恆常性維持相關蛋白質之藥物一併使用的癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之候補物質。 On the other hand, when the drug system which inhibits GST-π suppresses the above-mentioned constant-maintaining-related protein which exhibits a synthetic lethality to cancer cells together with inhibition of GST-π, the drug is inhibited. The cells show a synthetic lethal protein. Therefore, it is possible to screen for a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell which is used together with the above-described agent for inhibiting the maintenance of the related protein by the inhibition of GST-π. In other words, it is possible to suppress a GST-π substance to be a candidate for a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell used together with the drug for inhibiting the maintenance of a protein related to the constantity.

例如，作為癌細胞之一例，使受檢物質接觸表現變異型KRAS之細胞，並測定該細胞中之GST-π之表現量。於與在受檢物質之非存在下所測得之表現量相比，接觸受檢物質時之表現量降低之情形時，可選擇該受檢物質作為抑制GST-π之藥物之候補物質。 For example, as an example of a cancer cell, a test substance is brought into contact with a cell expressing a variant KRAS, and the amount of expression of GST-π in the cell is measured. When the amount of expression when the test substance is contacted is lowered as compared with the amount of expression measured in the absence of the test substance, the test substance can be selected as a candidate substance for the GST-π-inhibiting drug.

同樣地，可將對GST-π之抑制及對若與GST-π一併被抑制則對癌細胞顯示出合成致死性的恆常性維持相關蛋白質之抑制均作為指標，而篩選癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑。即，可抑制GST-π且上述可抑制恆常性維持相關蛋白質之物質係癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之候補物質。 Similarly, the inhibition of GST-π and the inhibition of the growth-related protein which exhibits a synthetic lethality to cancer cells when combined with GST-π can be used as an index to screen cells of cancer cells. Death inducer and/or cell proliferation inhibitor. In other words, it is possible to suppress GST-π and to suppress the cell death inducing agent and/or the cell proliferation inhibitor candidate substance of the cancer cell of the substance which maintains the related protein.

例如，作為癌細胞之一例，使受檢物質接觸表現變異型KRAS之細胞，並測定該細胞中之GST-π之表現量及上述恆常性維持相關蛋白 質之表現量。於與在受檢物質之非存在下所測得之各表現量相比，接觸受檢物質時之各表現量均降低之情形時，可選擇該受檢物質作為抑制GST-π且抑制若與GST-π一併被抑制則對癌細胞顯示出合成致死性之恆常性維持相關蛋白質的藥物之候補物質。 For example, as an example of a cancer cell, a test substance is brought into contact with a cell expressing a variant KRAS, and the amount of GST-π expression in the cell and the above-described constant maintenance related protein are measured. The amount of performance. When the amount of each of the expressions when the test substance is contacted is lowered as compared with the amount of each of the measured substances in the presence of the test substance, the test substance may be selected as the GST-π inhibition and the inhibition is When GST-π is inhibited together, the cancer cells exhibit a synthetic lethality and a candidate substance for the drug that maintains the relevant protein.

此處，作為受檢物質，並無任何限定，可為任何物質。作為受檢物質，可為單獨之物質，亦可為包含複數種構成成分之混合物。作為受檢物質，可為例如微生物或來自培養液之萃取物般包含未鑑定之物質之構成，亦可為以特定組成比包含已知組合物之構成。又，作為受檢物質，可為蛋白質、核酸、脂質、多糖類、有機化合物及無機化合物之任一者。 Here, the substance to be tested is not limited, and may be any substance. The substance to be tested may be a single substance or a mixture containing a plurality of constituent components. The test substance may be a composition including an unidentified substance such as a microorganism or an extract derived from a culture solution, or may be a composition containing a known composition at a specific composition ratio. Further, the test substance may be any of a protein, a nucleic acid, a lipid, a polysaccharide, an organic compound, and an inorganic compound.

[實施例] [Examples]

以下，藉由實施例更詳細地說明本發明，本發明之技術範圍不受以下實施例所限定。 Hereinafter, the present invention will be described in more detail by way of examples, but the technical scope of the present invention is not limited by the following examples.

[實驗1]因siRNA引起之GST-π及P21之敲減 [Experiment 1] GST-π and P21 knockdown due to siRNA

作為癌細胞之例，將1×105個M7609細胞(KRAS變異人類大腸癌細胞)及PANC-1細胞(KRAS變異人類胰腺癌細胞)接種至6cm培養皿中，於添加有10%胎牛血清(Fetal bovine serum、FBS)及0.5%L-麩胺酸之洛斯維帕克紀念研究所(Roswell Park Memorial Institute 1640、RPMI 1640、Sigma公司)中培養18小時。培養條件只要無特別說明，則於37℃、5%CO2下進行。又，作為癌細胞之例，將0.5×105個A549細胞(KRAS變異人類肺癌細胞)接種至6cm培養皿中，於添加有10%FBS及1%L-麩胺酸之杜貝可改良伊格爾培養基(Dulbecco's modified Eagle's medium、DMEM、Sigma公司)中培養18小時。進而，作為癌細胞之例，將1×105個MIA PaCa-2細胞(KRAS變異人類胰腺癌細胞)接種至6cm培養皿中，於添加有10%FBS及1%L-麩胺酸之DMEM中培養18小時。進而，作為癌細胞之例，將0.5×105個HCT116 細胞(KRAS變異人類大腸癌細胞)接種至6cm培養皿中，於添加有10%FBS及0.5%L-麩胺酸之McCoy's 5A培養基(McCoy、Sigma公司)中培養18小時。 As an example of the cancer cells, the 1 × 10 5 th M7609 cells (human colon cancer cells the KRAS mutation) and PANC-1 cells (human pancreatic cancer cells the KRAS mutation) were seeded into 6cm petri dish supplemented with 10% fetal calf serum (Fetal bovine serum, FBS) and 0.5% L-glutamic acid Los Angeles Park Memorial Institute (Roswell Park Memorial Institute 1640, RPMI 1640, Sigma) were cultured for 18 hours. The culture conditions were carried out at 37 ° C under 5% CO 2 unless otherwise specified. Further, as an example of cancer cells, 0.5 × 10 5 A549 cells (KRAS mutant human lung cancer cells) were inoculated into a 6 cm culture dish, and Dube can be modified with 10% FBS and 1% L-glutamic acid. The cells were cultured for 18 hours in Dulbecco's modified Eagle's medium, DMEM, and Sigma. Further, as an example of a cancer cell, 1 × 10 5 MIA PaCa-2 cells (KRAS mutant human pancreatic cancer cells) were inoculated into a 6 cm culture dish, and DMEM supplemented with 10% FBS and 1% L-glutamic acid was added. Train for 18 hours. Further, as an example of cancer cells, 0.5 × 10 5 HCT116 cells (KRAS mutant human colon cancer cells) were inoculated into a 6 cm culture dish, and McCoy's 5A medium supplemented with 10% FBS and 0.5% L-glutamic acid ( Cultured in McCoy, Sigma) for 18 hours.

於本實驗中，首先對已達到20~30%融合之PANC-1、A549或MIA PaCa-2細胞使用脂質體RNAiMAX(Life Technologies公司)，藉由以下方式對GST-π siRNA及/或P21 siRNA進行轉染。 In this experiment, liposomal RNAiMAX (Life Technologies) was first used for PANC-1, A549 or MIA PaCa-2 cells that have reached 20-30% fusion, and GST-π siRNA and/or P21 siRNA were used in the following manner. Transfection.

轉染用之脂質體/siRNA混合溶液係藉由以下方式製作。首先，製備將15μL之脂質體RNAiMAX與485μL之OPTI-MEM(Sigma公司)混合而成之脂質體溶液。其次，製備將特定量之50μM siRNA以OPTI-MEM定容為500μL之siRNA溶液(例如於製作使用最終濃度50nM之siRNA溶液之情形時，將6μL之50μM siRNA及494μL之OPTI-MEM混合)，將其與上述脂質體溶液混合，於室溫下靜置15分鐘。再者，siRNA係使用以下者。再者，於下述記載中，大寫字母意指RNA、小寫字母意指DNA。 The liposome/siRNA mixed solution for transfection was produced in the following manner. First, a liposome solution in which 15 μL of liposome RNAiMAX and 485 μL of OPTI-MEM (Sigma) were mixed was prepared. Next, prepare a siRNA solution in which a specific amount of 50 μM siRNA is made up to 500 μL in OPTI-MEM (for example, when preparing a siRNA solution having a final concentration of 50 nM, 6 μL of 50 μM siRNA and 494 μL of OPTI-MEM) will be prepared. This was mixed with the above liposome solution and allowed to stand at room temperature for 15 minutes. Further, the following were used for the siRNA system. Further, in the following description, uppercase letters mean RNA and lowercase letters mean DNA.

GST-π siRNA： GST-π siRNA:

正義鏈：GGGAGGCAAGACCUUCAUUtt(序列編號31) Justice chain: GGGAGGCAAGACCUUCAUUtt (sequence number 31)

反義鏈：AAUGAAGGUCUUGCCUCCCtg(序列編號32) Antisense strand: AAUGAAGGUCUUGCCUCCCtg (sequence number 32)

P21 siRNA： P21 siRNA:

正義鏈：UCCUAAGAGUGCUGGGCAUtt(序列編號33) Justice chain: UCCUAAGAGUGCUGGGCAUtt (sequence number 33)

反義鏈：AUGCCCAGCACUCUUAGGAtt(序列編號34) Antisense strand: AUGCCCAGCACUCUUAGGAtt (sequence number 34)

對照siRNA： Control siRNA:

正義鏈：ACGUGACACGUUCGGAGAAtt(序列編號35) Justice chain: ACGUGACACGUUCGGAGAAtt (sequence number 35)

反義鏈：UUCUCCGAACGUGUCACGUtt(序列編號36) Antisense strand: UUCUCCGAACGUGUCACGUtt (sequence number 36)

GST-π siRNA-2： GST-π siRNA-2:

正義鏈：UCUCCCUCAUCUACACCAAtt(序列編號37) Justice chain: UCCCCCACUUCACACCAAtt (sequence number 37)

反義鏈：UUGGUGUAGAUGAGGGAGAtg(序列編號38) Antisense strand: UUGGUGUAGAUGAGGGAGAtg (sequence number 38)

將GST-π siRNA及P21 siRNA以各自50nM之最終濃度，將GST-π siRNA或P21 siRNA以50nM之最終濃度(均以最終濃度50nM添加對照siRNA)，以及將GST-π siRNA以100nM之最終濃度(未添加對照siRNA)，分別添加至包含PANC-1、MIA PaCa-2細胞或A549細胞之培養皿中。作為對照，使用以100nM之最終濃度添加對照siRNA者。於不更換培養基而培養1天時間後，使用7300實時PCR系統(Applied Bio Systems公司)，藉由定量PCR法而定量GST-π mRNA量及P21 mRNA量。將結果示於圖1。如圖1所示，明確藉由siRNA而敲減GST-π，增加P21 mRNA量。 GST-π siRNA and P21 siRNA were added to GST-π siRNA or P21 siRNA at a final concentration of 50 nM (both at a final concentration of 50 nM plus control siRNA) and GST-π siRNA at a final concentration of 100 nM. (No control siRNA was added) and added to a Petri dish containing PANC-1, MIA PaCa-2 cells or A549 cells, respectively. As a control, a control siRNA was added at a final concentration of 100 nM. After culturing for 1 day without changing the medium, the amount of GST-π mRNA and the amount of P21 mRNA were quantified by a quantitative PCR method using a 7300 real-time PCR system (Applied Bio Systems). The results are shown in Fig. 1. As shown in Fig. 1, it was clarified that GST-π was knocked down by siRNA to increase the amount of P21 mRNA.

又，關於在包含A549細胞或MIA PaCa-2細胞之培養皿中以50nM之最終濃度分別添加有GST-π siRNA或對照siRNA的實例，自添加GST-π siRNA或對照siRNA之日起至第4天為止，每天同樣地定量P21 mRNA量。將結果示於圖2。如圖2所示，明確若藉由siRNA敲減GST-π，則P21 mRNA之表現量經時性地增加。 Further, regarding the addition of GST-π siRNA or control siRNA at a final concentration of 50 nM in a culture dish containing A549 cells or MIA PaCa-2 cells, from the date of addition of GST-π siRNA or control siRNA to the 4th The amount of P21 mRNA was quantified equally every day until day. The results are shown in Figure 2. As shown in Fig. 2, it is clear that if GST-π is knocked down by siRNA, the expression amount of P21 mRNA increases with time.

另一方面，驗證因GST-π siRNA及/或P21 siRNA所產生之對細胞數之影響。首先，將GST-π siRNA及P21 siRNA以各自50nM之最終濃度，將GST-π siRNA或P21 siRNA以50nM之最終濃度(均以最終濃度50nM添加對照siRNA)，添加至包含PANC-1、MIA PaCa-2細胞或A549細胞之培養皿中。作為對照，使用以100nM之最終濃度添加對照siRNA者。不更換培養基而培養5天時間後，以胰蛋白酶處理將細胞自培養皿剝離並採取，計數細胞數。將結果示於圖3。如圖3所示可知，於使用GST-π siRNA或P21 siRNA將各個GST-π及P21單獨敲減之情形時，雖然抑制細胞之增殖，但無法自接種細胞數減少細胞數。但是，可知若使用GST-π siRNA及P21 siRNA將GST-π及P21一併敲減，則於表現變異KRAS之PANC-1細胞及MIA PaCa-2細胞中不僅可抑制增殖，亦可誘導細胞死亡。 On the other hand, the effect on the number of cells produced by GST-π siRNA and/or P21 siRNA was examined. First, GST-π siRNA and P21 siRNA were added to GST-π siRNA or P21 siRNA at a final concentration of 50 nM (both at a final concentration of 50 nM plus control siRNA) at a final concentration of 50 nM, respectively, to include PANC-1, MIA PaCa. -2 cells or culture dishes in A549 cells. As a control, a control siRNA was added at a final concentration of 100 nM. After culturing for 5 days without changing the medium, the cells were peeled off from the culture dish by trypsin treatment, and the number of cells was counted. The results are shown in Fig. 3. As shown in Fig. 3, when GST-π and P21 were knocked down by GST-π siRNA or P21 siRNA alone, although the proliferation of cells was inhibited, the number of cells could not be reduced from the number of cells inoculated. However, it can be seen that when GST-π and P21 siRNA are used to knock down GST-π and P21 together, it is possible to inhibit proliferation and induce cell death in PANC-1 cells and MIA PaCa-2 cells exhibiting variant KRAS. .

再者，由圖3認為，表現變異KRAS之A549細胞不會藉由上述處理而誘導細胞死亡。因此，對於增加GST-π siRNA及P21 siRNA之轉染之次數而表現變異KRAS之A549細胞及HCT116細胞，驗證因GST-π siRNA及/或P21 siRNA所產生之對細胞數之影響。 Furthermore, it is considered from Fig. 3 that A549 cells exhibiting a variant KRAS do not induce cell death by the above treatment. Therefore, A549 cells and HCT116 cells expressing KRAS mutations were added to increase the number of transfections of GST-π siRNA and P21 siRNA, and the effect on the number of cells by GST-π siRNA and/or P21 siRNA was examined.

首先，對於PANC-1細胞、MIA PaCa-2細胞、HCT116細胞，GST-π siRNA及P21 siRNA以各自25nM之最終濃度，將GST-π siRNA或P21 siRNA以25nM之最終濃度(以25nM之最終濃度添加任一對照siRNA)，對於A549細胞，將GST-π siRNA及P21 siRNA以各自50nM之最終濃度，將GST-π siRNA或P21 siRNA以50nM之最終濃度(以50nM之最終濃度添加對照siRNA)，分別添加至培養皿中。作為對照，對於PANC-1細胞、MIA PaCa-2細胞、HCT116細胞，將對照siRNA以50nM之最終濃度進行添加，對於A549細胞，以100nM之最終濃度添加。於2天後及4天後，更換培養基(PANC-1細胞係採用添加有10%FBS之RPMI 1640，A549細胞及MIA PaCa-2細胞係採用添加有10%FBS之DMEM，HCT116細胞係採用添加有10%FBS之McCoy)，再次將GST-π siRNA或P21 siRNA分別添加至培養皿中，對於PANC-1細胞、MIA PaCa-2細胞、HCT116細胞，以25nM之最終濃度(以25nM之最終濃度添加任一對照siRNA)，對於A549細胞，以50nM之最終濃度(以50nM之最終濃度添加對照siRNA)分別添加至培養皿中。此時，作為對照，對於PANC-1、MIA PaCa-2細胞以50nM添加對照siRNA，對於A549細胞以100nM之最終濃度添加對照siRNA。其後，不更換培養基而進行培養，自細胞接種7天後，將細胞以胰蛋白酶處理自培養皿剝離採取，計數細胞數。又，於本例中，拍攝細胞之相位差圖像。 First, for PANC-1 cells, MIA PaCa-2 cells, HCT116 cells, GST-π siRNA and P21 siRNA, GST-π siRNA or P21 siRNA at a final concentration of 25 nM at a final concentration of 25 nM (at a final concentration of 25 nM) Add any control siRNA), for A549 cells, GST-π siRNA and P21 siRNA at a final concentration of 50 nM each, GST-π siRNA or P21 siRNA at a final concentration of 50 nM (adding control siRNA at a final concentration of 50 nM), Add separately to the culture dish. As a control, control siRNA was added to PANC-1 cells, MIA PaCa-2 cells, and HCT116 cells at a final concentration of 50 nM, and A549 cells were added at a final concentration of 100 nM. After 2 days and 4 days, the medium was changed (PANC-1 cell line was supplemented with RPMI 1640 supplemented with 10% FBS, A549 cells and MIA PaCa-2 cell line were treated with DMEM supplemented with 10% FBS, and HCT116 cell line was added. GCo-π siRNA or P21 siRNA was added to the culture dish again with 10% FBS. For PANC-1 cells, MIA PaCa-2 cells, HCT116 cells, the final concentration was 25 nM (at a final concentration of 25 nM). Any control siRNA) was added and added to the culture dish for A549 cells at a final concentration of 50 nM (addition of control siRNA at a final concentration of 50 nM). At this time, as a control, control siRNA was added to PANC-1, MIA PaCa-2 cells at 50 nM, and control siRNA was added to A549 cells at a final concentration of 100 nM. Thereafter, the culture was carried out without changing the medium, and 7 days after the cells were inoculated, the cells were detached from the culture dish by trypsin treatment, and the number of cells was counted. Also, in this example, a phase difference image of the cells is taken.

對A549細胞、PANC-1細胞及MIA PaCa-2細胞測定細胞數，將結果示於圖4，對HCT116細胞測定細胞數，將結果示於圖5。又，將對A549細胞所拍攝之相位差圖像示於圖6，將對MIA PaCa-2細胞所拍攝 之相位差圖像示於圖7，將對PANC-1細胞所拍攝之相位差圖像示於圖8，將對HCT116細胞所拍攝之相位差圖像示於圖9。 The number of cells was measured for A549 cells, PANC-1 cells, and MIA PaCa-2 cells, and the results are shown in Fig. 4. The number of cells was measured for HCT116 cells, and the results are shown in Fig. 5. In addition, the phase difference image taken on A549 cells is shown in Fig. 6, and will be taken on MIA PaCa-2 cells. The phase difference image is shown in Fig. 7, and the phase difference image taken by the PANC-1 cells is shown in Fig. 8, and the phase difference image taken by the HCT116 cells is shown in Fig. 9.

如圖4及5所示而明確，若使用GST-π siRNA及P21 siRNA將GST-π及P21一併敲減3次，則於表現變異型KRAS之癌細胞(A549細胞、MIA PaCa-2細胞、PANC-1細胞、HCT116細胞)中，自細胞接種7天後，較最初接種之細胞數減少，而可誘導細胞死亡。 As shown in Fig. 4 and Fig. 5, when GST-π siRNA and P21 siRNA were used to knock down GST-π and P21 three times together, they were expressed in cancer cells (A549 cells, MIA PaCa-2 cells) expressing variant KRAS. In PANC-1 cells and HCT116 cells, after 7 days of cell inoculation, the number of cells initially inoculated was decreased, and cell death was induced.

又，如圖6~9所示，關於利用GST-π siRNA敲減了GST-π之表現變異型KRAS的細胞(A549細胞、MIA PaCa-2細胞、PANC-1細胞、HCT116細胞)，任一細胞種類均成為扁平且較大之細胞，因此可推測誘發了細胞老化。進而明確，於使用GST-π siRNA及P21 siRNA將GST-π及P21一併敲減之情形時，於GST-π敲減時可見之細胞老化狀之表現型消失。根據該結果認為，於使用GST-π siRNA及P21 siRNA將GST-π及P21一併敲減之情形時，利用P21敲減而抑制了因GST-π敲減所誘發之細胞老化。 Further, as shown in FIGS. 6 to 9, any of the cells expressing the variant KRAS (A549 cells, MIA PaCa-2 cells, PANC-1 cells, and HCT116 cells) which knocked down GST-π by GST-π siRNA, Cell types are flat and large cells, so it is speculated that cell aging is induced. Further, when GST-π and P21 were simultaneously knocked down by GST-π siRNA and P21 siRNA, the phenotype of the cell aging state which was observed at the time of GST-π knockdown disappeared. From the results, it was considered that when GST-π and P21 were knocked down together by GST-π siRNA and P21 siRNA, cell aging induced by GST-π knockdown was suppressed by P21 knockdown.

再者，驗證了藉由使用M7609細胞敲減GST-π，是否可誘導如圖6~9所示之細胞老化。首先，將GST-π siRNA以30nM之最終濃度添加至包含M7609細胞之培養皿中。於1天後及2天後，更換培養基(添加有10%FBS之RPMI 1640)，再次將GST-π siRNA以30nM之最終濃度添加至包含M7609細胞之培養皿中。其後，每隔1天更換培養基並進行培養，自細胞接種13天後，使用細胞老化β-半乳糖苷酶染色套組(Cell Signaling公司)，依據推薦操作流程對細胞進行染色，並拍攝相位差圖像。將結果示於圖10。如圖10所示，可知敲減GST-π之M7609細胞成為扁平且較大之細胞，此種表現型之細胞觀察到因β-半乳糖苷酶引起之藍色顯色，因此引起了細胞老化。 Furthermore, it was verified whether cell aging as shown in Figs. 6 to 9 can be induced by knocking down GST-π using M7609 cells. First, GST-π siRNA was added to a Petri dish containing M7609 cells at a final concentration of 30 nM. After 1 day and 2 days, the medium (RPMI 1640 supplemented with 10% FBS) was replaced, and GST-π siRNA was again added to a Petri dish containing M7609 cells at a final concentration of 30 nM. Thereafter, the medium was changed and cultured every other day, and 13 days after the cell inoculation, the cells were stained with a cell-aged β-galactosidase staining kit (Cell Signaling), and the cells were stained according to the recommended procedure. Poor image. The results are shown in Fig. 10. As shown in Fig. 10, it was found that the M7609 cells knocked down by GST-π became flat and large cells, and the cells of this phenotype observed blue coloration by β-galactosidase, thereby causing cell aging. .

又，藉由測定作為細胞凋亡誘導因子之PUMA基因之表現量，而驗證於表現變異型KRAS之癌細胞中藉由將GST-π及P21一併敲減而誘 導之細胞死亡是否細胞凋亡。 Further, by measuring the expression amount of the PUMA gene as an apoptosis-inducing factor, it was confirmed that the cancer cells exhibiting the variant KRAS were induced by knocking down GST-π and P21 together. Whether the cell death leads to apoptosis.

首先，將GST-π siRNA及P21 siRNA分別以50nM之最終濃度，將GST-π siRNA或p21 siRNA以50nM之最終濃度(均以最終濃度50nM添加對照siRNA)，分別添加至包含A549細胞、MIA PaCa-2細胞之培養皿中。作為對照，將對照siRNA以100nM之最終濃度進行添加。不更換培養基而培養1天時間後，使用7300實時PCR系統(Applied Bio Systems公司)，藉由定量PCR法而定量PUMA mRNA量。 First, GST-π siRNA and P21 siRNA were added to GST-π siRNA or p21 siRNA at a final concentration of 50 nM (both at a final concentration of 50 nM plus control siRNA) at a final concentration of 50 nM, respectively, to A549 cells, MIA PaCa. -2 cells in a petri dish. As a control, control siRNA was added at a final concentration of 100 nM. After culturing for 1 day without changing the medium, the amount of PUMA mRNA was quantified by a quantitative PCR method using a 7300 real-time PCR system (Applied Bio Systems).

將結果示於圖11。如圖11所示可知，藉由使用GST-π siRNA及P21 siRNA將GST-π及p21一併敲減，作為細胞凋亡促進因子之PUMA之mRNA量大幅度增加。由該結果可知，藉由將GST-π及P21一併敲減而誘導之細胞死亡為細胞凋亡。 The results are shown in Fig. 11. As shown in Fig. 11, it was found that GST-π and p21 were knocked down together by GST-π siRNA and P21 siRNA, and the amount of mRNA of PUMA as an apoptosis promoting factor was greatly increased. From this result, it was revealed that cell death induced by knocking down GST-π and P21 together was apoptosis.

再者，細胞內存在細胞凋亡相關蛋白質群。細胞凋亡相關蛋白質大致分成細胞凋亡抑制蛋白質群及細胞凋亡誘導蛋白質群之2種。細胞凋亡抑制蛋白質群包括Bcl-2、Bcl-XL、Bcl-W、MCL-1及Bcl-B等。又，細胞凋亡誘導蛋白質群包括Bax、Bak、BOK、BIM、BID、BAD、NOXA及PUMA等。一般而言，Bcl-2、Bcl-XL、MCL-1等細胞凋亡抑制蛋白質存在於線粒體外壁，抑制細胞色素C之釋放，而抑制細胞凋亡。另一方面，Bax、BIM、BID及BAD等細胞凋亡誘導蛋白質群存在於細胞質，根據死亡訊號向線粒體外壁移行，促進細胞色素C之釋放，而誘導細胞凋亡。 Furthermore, there are apoptotic-associated protein groups in the cells. The apoptosis-related protein is roughly classified into two types, an apoptosis inhibitory protein group and an apoptosis-inducing protein group. The apoptosis inhibitory protein group includes Bcl-2, Bcl-XL, Bcl-W, MCL-1, and Bcl-B. Further, the apoptosis-inducing protein group includes Bax, Bak, BOK, BIM, BID, BAD, NOXA, PUMA, and the like. In general, apoptosis-inhibiting proteins such as Bcl-2, Bcl-XL, and MCL-1 are present on the outer wall of mitochondria, inhibiting the release of cytochrome C and inhibiting apoptosis. On the other hand, apoptosis-inducing protein groups such as Bax, BIM, BID, and BAD exist in the cytoplasm, and migrate to the mitochondrial outer wall according to the death signal to promote the release of cytochrome C and induce apoptosis.

又，p53若因DNA損傷等而活化，則促進Bax、NOXA、PUMA之轉錄，而誘導細胞凋亡。尤其是PUMA係作為以p53活化之細胞凋亡誘導蛋白質而單離之蛋白質，PUMA與Bcl-2直接結合，藉此抑制Bcl-2之細胞凋亡抑制作用，而誘導細胞向細胞凋亡。 Further, when p53 is activated by DNA damage or the like, transcription of Bax, NOXA, and PUMA is promoted to induce apoptosis. In particular, PUMA is a protein that is isolated by p53-activated apoptosis-inducing protein, and PUMA directly binds to Bcl-2, thereby inhibiting apoptosis inhibition of Bcl-2 and inducing apoptosis of cells.

以上，根據實驗1之結果顯示，若使抑制GST-π之藥劑及抑制P21之藥劑作用於癌細胞，則可大幅度抑制細胞增殖，進而強力誘導細胞 死亡。再者，即便使抑制GST-π之藥劑單獨作用於癌細胞，亦可抑制細胞增殖，但無法誘導細胞死亡，即便使抑制P21之藥劑單獨作用於該細胞，亦為可略微抑制細胞增殖之程度。因此，藉由使該等藥劑一併作用於癌細胞可誘導細胞死亡之情況可謂預想不到之效果。 As described above, according to the results of Experiment 1, when the agent that inhibits GST-π and the agent that inhibits P21 act on cancer cells, cell proliferation can be greatly suppressed, and cells can be strongly induced. death. Further, even if the agent for inhibiting GST-π acts alone on cancer cells, cell proliferation can be inhibited, but cell death cannot be induced, and even if the agent that inhibits P21 acts alone on the cells, the degree of cell proliferation can be slightly suppressed. . Therefore, the effect of inducing cell death by causing these agents to act together on cancer cells is an unexpected effect.

[實驗2] [Experiment 2]

於實驗1中，使用GST-π siRNA及P21 siRNA對針對癌細胞之合成致死性進行了實證。於本實驗2中，對藉由與GST-π一併抑制而顯示出合成致死性之細胞週期調節蛋白質進行了篩選。 In Experiment 1, GST-π siRNA and P21 siRNA were used to demonstrate the lethality of cancer cells. In the experiment 2, a cell cycle-regulating protein exhibiting synthetic lethality by inhibition with GST-π was screened.

首先，利用添加有10%FBS及1%L-麩胺酸之DMEM而製備1×104個/mL之MIA PaCa-2細胞懸浮液，將其於96孔培養盤之各孔中各接種100μL後，於添加有10%FBS及1%L-麩胺酸之DMEM中培養18小時。對已達到20~30%融合之MIA PaCa-2細胞使用脂質體RNAiMAX，藉由以下方式對GST-π siRNA-2及/或針對標靶基因之siRNA進行轉染。 First, a 1×10 4 /mL MIA PaCa-2 cell suspension was prepared by using DMEM supplemented with 10% FBS and 1% L-glutamic acid, and each was inoculated with 100 μL in each well of a 96-well culture plate. Thereafter, it was cultured for 18 hours in DMEM supplemented with 10% FBS and 1% L-glutamic acid. The liposome RNAiMAX was used for MIA PaCa-2 cells that had reached 20-30% confluence, and GST-π siRNA-2 and/or siRNA against the target gene were transfected in the following manner.

轉染用之脂質體/siRNA混合溶液係藉由以下方式製作。首先，於人類siGENOME siRNA庫-細胞週期控制-SMARTpool(Dharmacon公司)所含之各siRNA0.1nmol中添加51μL之無DNase水(Ambion公司)，於室溫下靜置90分鐘。製備於該siRNA水溶液中添加有19.9μL之OPTI-MEM的siRNA溶液(溶液A)。其次，將50μM GST-π siRNA-2水溶液及50μM對照siRNA水溶液分別以OPTI-MEM稀釋至10倍，製成GST-π siRNA-2之5μM及對照siRNA之5μM之稀釋溶液(溶液B)，將溶液A 31.2μL與溶液B 8.8μL(溶液C)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液D)。其次，將溶液C 37.5μL與溶液D 37.5μL混合，於室溫下靜置15分鐘(溶液E)。將溶液E各添加10μL，添加至培養MIA-PaCa-2細胞之96孔板之各孔中。 The liposome/siRNA mixed solution for transfection was produced in the following manner. First, 51 μL of DNase-free water (Ambion) was added to 0.1 nm of each siRNA contained in the human siGENOME siRNA library-cell cycle control-SMARTpool (Dharmacon), and allowed to stand at room temperature for 90 minutes. A siRNA solution (solution A) containing 19.9 μL of OPTI-MEM was added to the siRNA aqueous solution. Next, 50 μM GST-π siRNA-2 aqueous solution and 50 μM control siRNA aqueous solution were diluted 10-fold in OPTI-MEM to prepare a 5 μM GST-π siRNA-2 and 5 μM diluted solution of siRNA (solution B). Solution A 31.2 μL was mixed with Solution B 8.8 μL (Solution C). Next, a liposome solution (solution D) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, 37.5 μL of the solution C was mixed with 37.5 μL of the solution D, and allowed to stand at room temperature for 15 minutes (solution E). 10 μL of each of Solution E was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured.

另外製備於50μM對照siRNA水溶液(5.5μL)中混合有OPTI- MEM(189.5μL)之溶液(溶液F)。其次，將50μM對照siRNA水溶液以OPTI-MEM稀釋至10倍，而製成對照siRNA之5μM之稀釋溶液(溶液G)，將溶液F 31.2μL與溶液G 8.8μL(溶液H)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液I)。其次，將溶液H 37.5μL與溶液I 37.5μL混合，於室溫下靜置15分鐘(溶液J)。將溶液J各10μL添加至培養MIA-PaCa-2細胞之96孔板之各孔中，設為對照。其後，於添加有10%FBS及1%L-麩胺酸之DMEM中進行培養。5天後，使用CyQUANT NF細胞增殖分析套組(Invitrogen公司)進行增殖評價試驗。 In addition, prepared in a 50 μM control siRNA aqueous solution (5.5 μL) mixed with OPTI- A solution of MEM (189.5 μL) (solution F). Next, 50 μM of the control siRNA aqueous solution was diluted 10-fold with OPTI-MEM to prepare a 5 μM diluted solution of the control siRNA (solution G), and the solution F 31.2 μL was mixed with the solution G 8.8 μL (solution H). Next, a liposome solution (solution I) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, the solution H 37.5 μL was mixed with the solution I 37.5 μL, and allowed to stand at room temperature for 15 minutes (solution J). 10 μL of each of the solution J was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured, and it was set as a control. Thereafter, the culture was carried out in DMEM supplemented with 10% FBS and 1% L-glutamic acid. Five days later, a proliferation evaluation test was performed using a CyQUANT NF cell proliferation assay kit (Invitrogen).

首先，於22μL之CyQUANT NF染色試劑中添加1×HBSS緩衝液，而製備CyQUANT NF細胞增殖分析之染色反應液。吸去上述經轉染之細胞之培養基，添加50μL之染色反應液。於37℃下靜置30分鐘後，觀察於激發波長480nm下進行激發時之螢光波長520nm。 First, a 1 × HBSS buffer was added to 22 μL of CyQUANT NF staining reagent to prepare a staining reaction solution for CyQUANT NF cell proliferation assay. The medium of the above transfected cells was aspirated, and 50 μL of the staining reaction solution was added. After standing at 37 ° C for 30 minutes, the fluorescence wavelength at 520 nm when excitation was performed at an excitation wavelength of 480 nm was observed.

將結果示於圖12。如圖12所示，對編碼細胞週期調節蛋白質之170種基因篩選與GST-π之合成致死性，結果除了實驗1中所實證之P21以外，篩選出ATM、CDC25A、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3及MCMDC1作為藉由與GST-π一併被抑制則顯示出合成致死性之細胞週期調節蛋白質。其中，關於P21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1，於單獨進行抑制之情形時，為可略微抑制細胞增殖之程度(增殖抑制率未達20%)，而選作若與GST-π一併被抑制則首次顯示出合成致死性之細胞週期調節蛋白質。因此，認為選自該等P21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1中之抑制細胞週期調節蛋白質的藥劑於單獨使用時毒性非常低而安全性優異。 The results are shown in Fig. 12. As shown in Figure 12, the 170 genes encoding the cell cycle regulatory proteins were screened for lethality with GST-π, and the results were selected for ATM, CDC25A, PRKDC, RBBP8, SKP2, and MCM10 in addition to the P21 demonstrated in Experiment 1. RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, and MCMDC1 are cell cycle-regulating proteins which exhibit synthetic lethality by being inhibited together with GST-π. Among them, P21, RNPC1, CCNL1, MCM8, CCNB3, and MCMDC1, when inhibited alone, can slightly inhibit cell proliferation (the proliferation inhibition rate is less than 20%), and is selected as GST-π When inhibited, it shows for the first time a synthetic lethal cell cycle regulatory protein. Therefore, it is considered that the agent for inhibiting cell cycle regulatory proteins selected from the above P21, RNPC1, CCNL1, MCM8, CCNB3, and MCMDC1 is very low in toxicity and excellent in safety when used alone.

[實驗3] [Experiment 3]

於實驗2中，篩選藉由與GST-π一併抑制而顯示出合成致死性之 細胞週期調節蛋白質。於本實驗3中，製成具有篩選藉由與GST-π一併抑制而顯示出合成致死性之抗細胞凋亡功能之蛋白質。 In Experiment 2, the screening showed synthetic lethality by inhibition with GST-π. Cell cycle regulatory proteins. In the experiment 3, a protein having an anti-apoptotic function which exhibits a synthetic lethality by inhibition with GST-π was prepared.

首先，利用添加有10%FBS及1%L-麩胺酸之DMEM而製備1×104個/mL之MIA PaCa-2細胞懸浮液，將其於96孔培養盤之各孔中各接種100μL後，於添加有10%FBS及1%L-麩胺酸之DMEM中培養18小時。對已達到20~30%融合之MIA PaCa-2細胞使用脂質體RNAiMAX，藉由以下方式對GST-π siRNA-2及/或針對標靶基因之siRNA進行轉染。 First, a 1×10 4 /mL MIA PaCa-2 cell suspension was prepared by using DMEM supplemented with 10% FBS and 1% L-glutamic acid, and each was inoculated with 100 μL in each well of a 96-well culture plate. Thereafter, it was cultured for 18 hours in DMEM supplemented with 10% FBS and 1% L-glutamic acid. The liposome RNAiMAX was used for MIA PaCa-2 cells that had reached 20-30% confluence, and GST-π siRNA-2 and/or siRNA against the target gene were transfected in the following manner.

轉染用之脂質體/siRNA混合溶液係藉由以下方式製作。首先，於獨自選拔認為具有抗細胞凋亡功能之140種基因的定製siRNA庫(siGENOME SMARTpool Cherry-pick Library、Dharmacon公司)所含之各siRNA 0.1nmol中添加51μL之無DNase水(Ambion公司)，於室溫下靜置90分鐘。製備於該siRNA水溶液中添加有19.9μL之OPTI-MEM之siRNA溶液(溶液A)。其次，將50μM GST-π siRNA-2水溶液及50μM對照siRNA水溶液分別利用OPTI-MEM稀釋至10倍，而製成GST-π siRNA-2之5μM及對照siRNA之5μM溶液(溶液B)，將溶液A 31.2μL與溶液B 8.8μL(溶液C)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液D)。其次，將溶液C 37.5μL與溶液D 37.5μL混合，於室溫下靜置15分鐘(溶液E)。將溶液E以每次10μL添加至培養MIA-PaCa-2細胞之96孔板之各孔中。 The liposome/siRNA mixed solution for transfection was produced in the following manner. First, 51 μL of DNase-free water (Ambion) was added to 0.1 nmol of each siRNA contained in a custom siRNA library (siGENOME SMARTpool Cherry-pick Library, Dharmacon) which is considered to have 140 genes having anti-apoptotic function. , let stand at room temperature for 90 minutes. A siRNA solution (solution A) of 19.9 μL of OPTI-MEM was added to the siRNA aqueous solution. Next, 50 μM GST-π siRNA-2 aqueous solution and 50 μM control siRNA aqueous solution were diluted 10-fold with OPTI-MEM to prepare 5 μM of GST-π siRNA-2 and 5 μM solution of control siRNA (solution B). A 31.2 μL was mixed with Solution B 8.8 μL (solution C). Next, a liposome solution (solution D) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, 37.5 μL of the solution C was mixed with 37.5 μL of the solution D, and allowed to stand at room temperature for 15 minutes (solution E). Solution E was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured at 10 μL each time.

另外製備在50μM之對照siRNA水溶液(5.5μL)中混合有OPTI-MEM(189.5μL)之溶液(溶液F)。其次，將50μM之對照siRNA水溶液以OPTI-MEM稀釋至10倍，而製成對照siRNA之5μM之稀釋溶液(溶液G)，將溶液F 31.2μL與溶液G 8.8μL(溶液H)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液I)。其次，將溶液H 37.5μL與溶液I 37.5μL混合，於室溫下靜置 15分鐘(溶液J)。將溶液J以每次10μL添加至培養MIA-PaCa-2細胞之96孔板之各孔中，作為對照。其後，於添加有10%FBS及1%L-麩胺酸之DMEM中進行培養。5天後，使用CyQUANT NF細胞增殖分析套組(Invitrogen公司)進行增殖評價試驗。 Further, a solution (solution F) of OPTI-MEM (189.5 μL) was mixed in 50 μM of a control siRNA aqueous solution (5.5 μL). Next, 50 μM of the control siRNA aqueous solution was diluted 10-fold with OPTI-MEM to prepare a 5 μM diluted solution of the control siRNA (solution G), and the solution F 31.2 μL was mixed with the solution G 8.8 μL (solution H). Next, a liposome solution (solution I) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, the solution H 37.5 μL was mixed with the solution I 37.5 μL, and allowed to stand at room temperature. 15 minutes (solution J). Solution J was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured at 10 μL each time as a control. Thereafter, the culture was carried out in DMEM supplemented with 10% FBS and 1% L-glutamic acid. Five days later, a proliferation evaluation test was performed using a CyQUANT NF cell proliferation assay kit (Invitrogen).

首先，製備在22μL之CyQUANT NF染色試劑中添加有11mL之1×HBSS緩衝液的CyQUANT NF細胞增殖分析之染色反應液。吸去上述經轉染之細胞之培養基，並添加50μL之染色反應液。於37℃下靜置30分鐘後，觀察於激發波長480nm下進行激發時之螢光波長520nm。 First, a staining reaction solution of CyQUANT NF cell proliferation assay in which 11 mL of 1×HBSS buffer was added to 22 μL of CyQUANT NF staining reagent was prepared. The medium of the above transfected cells was aspirated, and 50 μL of the staining reaction solution was added. After standing at 37 ° C for 30 minutes, the fluorescence wavelength at 520 nm when excitation was performed at an excitation wavelength of 480 nm was observed.

將結果示於圖13。如圖13所示，針對編碼與抗細胞凋亡相關之蛋白質之140種基因，篩選與GST-π之合成致死性，結果篩選出AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A作為與藉由與GST-π一併被抑制則顯示出合成致死性之抗細胞凋亡相關之蛋白質。 The results are shown in Fig. 13. As shown in Figure 13, the 140 genes encoding the proteins involved in anti-apoptosis were screened for lethality with GST-π, and the results were selected for AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1. BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A are proteins related to anti-apoptosis which exhibits synthetic lethality by being inhibited together with GST-π.

[實驗4] [Experiment 4]

於實驗2中，篩選藉由與GST-π一併抑制而顯示出合成致死性之細胞週期調節蛋白質，於實驗3中，篩選藉由與GST-π一併抑制而顯示出合成致死性之具有抗細胞凋亡功能的蛋白質。於本實驗4中，篩選與藉由與GST-π一併抑制而顯示出合成致死性之PI3K訊號傳遞路徑相關之蛋白質。 In Experiment 2, a cell cycle-regulating protein which exhibits a synthetic lethality by inhibition with GST-π was screened, and in Experiment 3, the screen showed a synthetic lethality by inhibition with GST-π. A protein that is resistant to apoptotic function. In Experiment 4, proteins related to the PI3K signal transmission pathway showing synthesis lethality by inhibition with GST-π were screened.

首先，利用添加有10%FBS及1%L-麩胺酸之DMEM而製備1×104個/mL之MIA PaCa-2細胞懸浮液，將其於96孔培養盤之各孔中各接種100μL後，於添加有10%FBS及1%L-麩胺酸之DMEM中培養18小時。對已達到20~30%融合之MIA PaCa-2細胞使用脂質體RNAiMAX，藉由以下方式對GST-π siRNA-2及/或針對標靶基因之siRNA進行轉染。 First, a 1×10 4 /mL MIA PaCa-2 cell suspension was prepared by using DMEM supplemented with 10% FBS and 1% L-glutamic acid, and each was inoculated with 100 μL in each well of a 96-well culture plate. Thereafter, it was cultured for 18 hours in DMEM supplemented with 10% FBS and 1% L-glutamic acid. The liposome RNAiMAX was used for MIA PaCa-2 cells that had reached 20-30% confluence, and GST-π siRNA-2 and/or siRNA against the target gene were transfected in the following manner.

藉由以下方式製作轉染用之脂質體/siRNA混合溶液。首先，於獨自選拔認為與PI3K訊號傳遞路徑相關之80種基因的定製siRNA庫(siGENOME SMARTpool Cherry-pick Library、Dharmacon公司)所含之各siRNA 0.1nmol中添加51μL之無DNase水(Ambion公司)，於室溫下靜置90分鐘。製備在該siRNA水溶液中添加有19.9μL之OPTI-MEM之siRNA溶液(溶液A)。其次，將50μM GST-π siRNA-2水溶液或50μM對照siRNA水溶液分別利用OPTI-MEM稀釋至10倍，而製成GST-π siRNA-2之5μM或對照siRNA之5μM溶液(溶液B)，將溶液A 31.2μL與溶液B 8.8μL(溶液C)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液D)。其次，將溶液C 37.5μL與溶液D 37.5μL混合，於室溫下靜置15分鐘(溶液E)。將溶液E以每次10μL添加至培養MIA-PaCa-2細胞之96孔板之各孔中。 A liposome/siRNA mixed solution for transfection was prepared in the following manner. First, 51 μL of DNase-free water (Ambion) was added to 0.1 nmol of each siRNA contained in a custom siRNA library (siGENOME SMARTpool Cherry-pick Library, Dharmacon) which is considered to be related to the PI3K signal transmission pathway. , let stand at room temperature for 90 minutes. A siRNA solution (solution A) in which 19.9 μL of OPTI-MEM was added to the siRNA aqueous solution was prepared. Next, 50 μM GST-π siRNA-2 aqueous solution or 50 μM control siRNA aqueous solution was diluted 10-fold with OPTI-MEM to prepare 5 μM of GST-π siRNA-2 or 5 μM solution of control siRNA (solution B). A 31.2 μL was mixed with Solution B 8.8 μL (solution C). Next, a liposome solution (solution D) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, 37.5 μL of the solution C was mixed with 37.5 μL of the solution D, and allowed to stand at room temperature for 15 minutes (solution E). Solution E was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured at 10 μL each time.

另外製備在50μM之對照siRNA水溶液(5.5μL)中混合有OPTI-MEM(189.5μL)之溶液(溶液F)。其次，將50μM對照siRNA水溶液以OPTI-MEM稀釋至10倍，而製成對照siRNA之5μM之稀釋溶液(溶液G)，將溶液F 31.2μL與溶液G 8.8μL(溶液H)混合。其次，製備將150μL之脂質體RNAiMAX與2.35mL之OPTI-MEM混合而成之脂質體溶液(溶液I)。其次，將溶液H 37.5μL與溶液I 37.5μL混合，於室溫下靜置15分鐘(溶液J)。將溶液J以每次10μL添加至培養MIA-PaCa-2細胞之96孔板之各孔中，作為對照。其後，於添加有10%FBS及1%L-麩胺酸之DMEM中進行培養。5天後，使用CyQUANT NF細胞增殖分析套組(Invitrogen公司)進行增殖評價試驗。 Further, a solution (solution F) of OPTI-MEM (189.5 μL) was mixed in 50 μM of a control siRNA aqueous solution (5.5 μL). Next, 50 μM of the control siRNA aqueous solution was diluted 10-fold with OPTI-MEM to prepare a 5 μM diluted solution of the control siRNA (solution G), and the solution F 31.2 μL was mixed with the solution G 8.8 μL (solution H). Next, a liposome solution (solution I) obtained by mixing 150 μL of liposome RNAiMAX with 2.35 mL of OPTI-MEM was prepared. Next, the solution H 37.5 μL was mixed with the solution I 37.5 μL, and allowed to stand at room temperature for 15 minutes (solution J). Solution J was added to each well of a 96-well plate in which MIA-PaCa-2 cells were cultured at 10 μL each time as a control. Thereafter, the culture was carried out in DMEM supplemented with 10% FBS and 1% L-glutamic acid. Five days later, a proliferation evaluation test was performed using a CyQUANT NF cell proliferation assay kit (Invitrogen).

首先，向22μL之CyQUANT NF染色試劑中添加11mL之1×HBSS緩衝液而製備CyQUANT NF細胞增殖分析之染色反應液。吸去上述經轉染之細胞之培養基，並添加50μL之染色反應液。於37℃下靜置30 分鐘後，觀察於激發波長480nm下進行激發時之螢光波長520nm。 First, 11 mL of 1×HBSS buffer was added to 22 μL of CyQUANT NF staining reagent to prepare a staining reaction solution for CyQUANT NF cell proliferation assay. The medium of the above transfected cells was aspirated, and 50 μL of the staining reaction solution was added. Allow to stand at 37 ° C 30 After a minute, the fluorescence wavelength at 520 nm when excitation was performed at an excitation wavelength of 480 nm was observed.

將結果示於圖14。如圖14所示，針對編碼與PI3K訊號傳遞路徑相關之蛋白質之80種基因，篩選與GST-π之合成致死性，結果篩選出MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF作為與藉由與GST-π一併被抑制則顯示出合成致死性之PI3K訊號傳遞路徑相關之蛋白質。其中，關於MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG及RAC1，明確藉由與GST-π一併加以抑制，細胞增殖抑制效果顯著較高。 The results are shown in Fig. 14. As shown in Figure 14, for the 80 genes encoding proteins related to the PI3K signal transmission pathway, the synthesis and lethality of GST-π were screened, and the results showed that MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF are proteins associated with the PI3K signal transmission pathway which exhibits synthetic lethality by being inhibited together with GST-π. Among them, regarding MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, and RAC1, it was confirmed that the cell proliferation inhibitory effect was remarkably high by suppressing together with GST-π.

[實驗5] [Experiment 5]

於本實驗5中，針對作為細胞週期調節蛋白質之MYLK(HEPATOLOGY,Vol.44,No.1,2006,152-163)，研究針對與GST-π一併抑制時之A549細胞(KRAS變異人類肺癌細胞)之合成致死性。 In this experiment 5, A549 cells (HEPATOLOGY, Vol. 44, No. 1, 2006, 152-163), which are cell cycle regulatory proteins, were studied for A549 cells (KRAS variant human lung cancer) when combined with GST-π inhibition. The synthesis of cells) is lethal.

首先，於轉染siRNA 1日之前，以成為0.25×105個/孔之方式將A549細胞與添加有10%FBS之DMEM(不含有抗生物質)2.25mL一併接種至各孔中。再者，於本實驗中，使用6孔之培養盤，對各樣品以三連進行。對所培養之A549細胞使用脂質體RNAiMAX，藉由以下方式對GST-π siRNA-3及/或針對MYLK之siRNA進行轉染(使用MYLKa及MYLKb之2種)。 First, A549 cells were inoculated into each well together with 2.25 mL of DMEM (without anti-biomass) supplemented with 10% FBS at a rate of 0.25 × 10 5 /well before the siRNA was transfected for 1 day. Further, in this experiment, a 6-well culture plate was used, and each sample was carried out in three stages. GST-π siRNA-3 and/or siRNA against MYLK were transfected with the liposome RNAiMAX of the cultured A549 cells (two types of MYLKa and MYLKb were used).

轉染用之脂質體/siRNA混合溶液係藉由以下方式製作。首先，將50nM之GST-π siRNA-3溶液與針對MYLK之siRNA溶液各0.5μL混合，準備添加有124μL之OPTI-MEM的siRNA溶液。再者，對於僅對照siRNA溶液、對照siRNA溶液與GST-π siRNA-3溶液之組合、對照siRNA溶液與針對MYLK之siRNA溶液之組合，以與siRNA相同濃度之方式準備siRNA溶液。又，準備將7.5μL之脂質體RNAiMAX與117.5 μL之OPTI-MEM混合而成之脂質體溶液。然後，將所準備之siRNA溶液與脂質體溶液加以混合，於室溫下靜置5分鐘。 The liposome/siRNA mixed solution for transfection was produced in the following manner. First, 50 μM of the GST-π siRNA-3 solution and 0.5 μL of the MYLK-containing siRNA solution were mixed, and a siRNA solution to which 124 μL of OPTI-MEM was added was prepared. Further, the siRNA solution was prepared in the same concentration as the siRNA for the combination of the control siRNA solution alone, the control siRNA solution and the GST-π siRNA-3 solution, the control siRNA solution and the MYLK siRNA solution. Also, prepare 7.5 μL of liposome RNAiMAX with 117.5 A liposome solution of μL of OPTI-MEM mixed. Then, the prepared siRNA solution was mixed with the liposome solution, and allowed to stand at room temperature for 5 minutes.

將所獲得之混合溶液逐滴滴加至孔中，最終將各孔設為2.5mL(siRNA之最終濃度為20nM)。其後，一面溫和地振盪一面於37℃、5%CO2之條件下培養75小時。培養結束後，以與實驗1~4相同之方式進行增殖評價試驗。將其結果示於圖15。如圖15所示而明確，藉由將作為細胞週期調節蛋白質之一的MYLK與GST-π一併加以抑制，顯示出針對癌細胞之合成致死性。即，根據圖15所示之結果明確，使抑制GST-π之藥劑及抑制MYLK之藥劑分別單獨作用於癌細胞時，細胞增殖抑制效果有限，但將抑制GST-π之藥劑及抑制MYLK之藥劑一併作用於癌細胞時，可非常強力地抑制細胞增殖。 The obtained mixed solution was added dropwise to the wells, and finally each well was set to 2.5 mL (the final concentration of siRNA was 20 nM). Thereafter, the mixture was gently shaken while being shaken at 37 ° C under 5% CO 2 for 75 hours. After the completion of the culture, the proliferation evaluation test was carried out in the same manner as in Experiments 1 to 4. The result is shown in Fig. 15. As shown in Fig. 15, it was confirmed that MYLK, which is one of the cell cycle regulatory proteins, was inhibited together with GST-π, and the synthesis lethality against cancer cells was exhibited. In other words, according to the results shown in Fig. 15, when the agent for inhibiting GST-π and the agent for inhibiting MYLK are each acted exclusively on cancer cells, the cell proliferation inhibiting effect is limited, but the GST-π inhibitor and the MYLK inhibitor are inhibited. When it acts on cancer cells together, it can inhibit cell proliferation very strongly.

再者，siRNA係使用以下者。再者，於下述記載中，大寫字母意指RNA，小寫字母意指DNA。 Further, the following were used for the siRNA system. Further, in the following description, uppercase letters mean RNA, and lowercase letters mean DNA.

GST-π siRNA-3： GST-π siRNA-3:

正義鏈：CCUUUUGAGACCCUGCUGUtt(序列編號109) Justice chain: CCUUUUGAGACCCUGCUGUtt (sequence number 109)

反義鏈：ACAGCAGGGUCUCAAAAGGtt(序列編號110) Antisense strand: ACAGCAGGGUCUCAAAAGGtt (sequence number 110)

MYLKa： MYLKa:

正義鏈：CUGGGGAAGAAGGUGAGUAtt(序列編號111) Justice chain: CUGGGGAAGAAGGUGAGUAtt (sequence number 111)

反義鏈：UACUCACCUUCUUCCCCAGtt(序列編號112) Antisense strand: UACUCACCUUCUUCCCCAGtt (sequence number 112)

MYLKb： MYLKb:

正義鏈：CAAGAUAGCCAGAGUUUAAtt(序列編號113) Justice chain: CAAGAUAGCCAGAGUUUAAtt (sequence number 113)

反義鏈：UUAAACUCUGGCUAUCUUGtt(序列編號114) Antisense chain: UUAAACUCUGGCUAUCUUGtt (sequence number 114)

本說明書中所引用之全部刊行物、專利及專利申請係直接藉由引用而併入本說明書中。 All publications, patents and patent applications cited in this specification are hereby incorporated by reference in their entirety.

<110> 日商日東電工股份有限公司 <110> Nissho Nitto Electric Co., Ltd.

<120> 細胞死亡誘導劑、細胞增殖抑制劑及起因於細胞增殖異常之疾病治療用醫藥組合物 <120> Cell death inducing agent, cell proliferation inhibitor, and pharmaceutical composition for treating diseases caused by abnormal cell proliferation

<130> PH-6256-PCT <130> PH-6256-PCT

<150> JP 2014-266198 <150> JP 2014-266198

<151> 2014-12-26 <151> 2014-12-26

<150> JP 2015-135494 <150> JP 2015-135494

<151> 2015-07-06 <151> 2015-07-06

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<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> misc_RNA <221> misc_RNA

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 35 <400> 35

<210> 36 <210> 36

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> misc_RNA <221> misc_RNA

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 36 <400> 36

<210> 37 <210> 37

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> misc_RNA <221> misc_RNA

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 37 <400> 37

<210> 38 <210> 38

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> misc_RNA <221> misc_RNA

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 38 <400> 38

<210> 39 <210> 39

<211> 2172 <211> 2172

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (252)..(1934) <222> (252)..(1934)

<400> 39 <400> 39

<210> 40 <210> 40

<211> 560 <211> 560

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 40 <400> 40

<210> 41 <210> 41

<211> 7492 <211> 7492

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (283)..(5667) <222> (283)..(5667)

<400> 41 <400> 41

<210> 42 <210> 42

<211> 1794 <211> 1794

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 42 <400> 42

<210> 43 <210> 43

<211> 2358 <211> 2358

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (54)..(2045) <222> (54)..(2045)

<400> 43 <400> 43

<210> 44 <210> 44

<211> 663 <211> 663

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 44 <400> 44

<210> 45 <210> 45

<211> 1556 <211> 1556

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (209)..(1249) <222> (209)..(1249)

<400> 45 <400> 45

<210> 46 <210> 46

<211> 346 <211> 346

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 46 <400> 46

<210> 47 <210> 47

<211> 2158 <211> 2158

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (228)..(1193) <222> (228)..(1193)

<400> 47 <400> 47

<210> 48 <210> 48

<211> 321 <211> 321

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 48 <400> 48

<210> 49 <210> 49

<211> 3782 <211> 3782

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (174)..(1748) <222> (174)..(1748)

<400> 49 <400> 49

<210> 50 <210> 50

<211> 524 <211> 524

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 50 <400> 50

<210> 51 <210> 51

<211> 2293 <211> 2293

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (583)..(1431) <222> (583)..(1431)

<400> 51 <400> 51

<210> 52 <210> 52

<211> 282 <211> 282

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 52 <400> 52

<210> 53 <210> 53

<211> 1551 <211> 1551

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (57)..(1145) <222> (57)..(1145)

<400> 53 <400> 53

<210> 54 <210> 54

<211> 362 <211> 362

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 54 <400> 54

<210> 55 <210> 55

<211> 912 <211> 912

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (17)..(772) <222> (17)..(772)

<400> 55 <400> 55

<210> 56 <210> 56

<211> 251 <211> 251

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 56 <400> 56

<210> 57 <210> 57

<211> 3885 <211> 3885

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (88)..(1125) <222> (88)..(1125)

<400> 57 <400> 57

<210> 58 <210> 58

<211> 345 <211> 345

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 58 <400> 58

<210> 59 <210> 59

<211> 2575 <211> 2575

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (367)..(1068) <222> (367)..(1068)

<400> 59 <400> 59

<210> 60 <210> 60

<211> 233 <211> 233

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 60 <400> 60

<210> 61 <210> 61

<211> 3060 <211> 3060

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (282)..(1634) <222> (282)..(1634)

<400> 61 <400> 61

<210> 62 <210> 62

<211> 450 <211> 450

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 62 <400> 62

<210> 63 <210> 63

<211> 10640 <211> 10640

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (466)..(1908) <222> (466)..(1908)

<400> 63 <400> 63

<210> 64 <210> 64

<211> 480 <211> 480

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 64 <400> 64

<210> 65 <210> 65

<211> 822 <211> 822

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (56)..(517) <222> (56)..(517)

<400> 65 <400> 65

<210> 66 <210> 66

<211> 153 <211> 153

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 66 <400> 66

<210> 67 <210> 67

<211> 5046 <211> 5046

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (259)..(2733) <222> (259)..(2733)

<400> 67 <400> 67

<210> 68 <210> 68

<211> 824 <211> 824

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 68 <400> 68

<210> 69 <210> 69

<211> 4107 <211> 4107

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (209)..(1261) <222> (209)..(1261)

<400> 69 <400> 69

<210> 70 <210> 70

<211> 350 <211> 350

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 70 <400> 70

<210> 71 <210> 71

<211> 4560 <211> 4560

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (626)..(3022) <222> (626)..(3022)

<400> 71 <400> 71

<210> 72 <210> 72

<211> 798 <211> 798

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 72 <400> 72

<210> 73 <210> 73

<211> 3215 <211> 3215

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (178)..(2415) <222> (178)..(2415)

<400> 73 <400> 73

<210> 74 <210> 74

<211> 745 <211> 745

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 74 <400> 74

<210> 75 <210> 75

<211> 2535 <211> 2535

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (141)..(1667) <222> (141)..(1667)

<400> 75 <400> 75

<210> 76 <210> 76

<211> 508 <211> 508

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 76 <400> 76

<210> 77 <210> 77

<211> 2785 <211> 2785

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (266)..(2368) <222> (266)..(2368)

<400> 77 <400> 77

<210> 78 <210> 78

<211> 700 <211> 700

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 78 <400> 78

<210> 79 <210> 79

<211> 7591 <211> 7591

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (159)..(6323) <222> (159)..(6323)

<400> 79 <400> 79

<210> 80 <210> 80

<211> 2054 <211> 2054

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 80 <400> 80

<210> 81 <210> 81

<211> 8733 <211> 8733

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (122)..(7771) <222> (122)..(7771)

<400> 81 <400> 81

<210> 82 <210> 82

<211> 2549 <211> 2549

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 82 <400> 82

<210> 83 <210> 83

<211> 3352 <211> 3352

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (80)..(1981) <222> (80)..(1981)

<400> 83 <400> 83

<210> 84 <210> 84

<211> 633 <211> 633

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 84 <400> 84

<210> 85 <210> 85

<211> 8743 <211> 8743

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (53)..(3781) <222> (53)..(3781)

<400> 85 <400> 85

<210> 86 <210> 86

<211> 1242 <211> 1242

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 86 <400> 86

<210> 87 <210> 87

<211> 2886 <211> 2886

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (185)..(1138) <222> (185)..(1138)

<400> 87 <400> 87

<210> 88 <210> 88

<211> 317 <211> 317

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 88 <400> 88

<210> 89 <210> 89

<211> 4093 <211> 4093

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (468)..(3377) <222> (468)..(3377)

<400> 89 <400> 89

<210> 90 <210> 90

<211> 969 <211> 969

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 90 <400> 90

<210> 91 <210> 91

<211> 7069 <211> 7069

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (162)..(3470) <222> (162)..(3470)

<400> 91 <400> 91

<210> 92 <210> 92

<211> 1102 <211> 1102

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 92 <400> 92

<210> 93 <210> 93

<211> 2398 <211> 2398

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (242)..(877) <222> (242)..(877)

<400> 93 <400> 93

<210> 94 <210> 94

<211> 211 <211> 211

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 94 <400> 94

<210> 95 <210> 95

<211> 1734 <211> 1734

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (113)..(1510) <222> (113)..(1510)

<400> 95 <400> 95

<210> 96 <210> 96

<211> 465 <211> 465

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 96 <400> 96

<210> 97 <210> 97

<211> 4076 <211> 4076

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (227)..(2077) <222> (227)..(2077)

<400> 97 <400> 97

<210> 98 <210> 98

<211> 616 <211> 616

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 98 <400> 98

<210> 99 <210> 99

<211> 4749 <211> 4749

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (1524)..(2177) <222> (1524)..(2177)

<400> 99 <400> 99

<210> 100 <210> 100

<211> 217 <211> 217

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 100 <400> 100

<210> 101 <210> 101

<211> 1843 <211> 1843

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (208)..(1566) <222> (208)..(1566)

<400> 101 <400> 101

<210> 102 <210> 102

<211> 452 <211> 452

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 102 <400> 102

<210> 103 <210> 103

<211> 2329 <211> 2329

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (627)..(950) <222> (627)..(950)

<400> 103 <400> 103

<210> 104 <210> 104

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 104 <400> 104

<210> 105 <210> 105

<211> 3724 <211> 3724

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (158)..(3364) <222> (158)..(3364)

<400> 105 <400> 105

<210> 106 <210> 106

<211> 1068 <211> 1068

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 106 <400> 106

<210> 107 <210> 107

<211> 4230 <211> 4230

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<220> <220>

<221> CDS <221> CDS

<222> (363)..(1889) <222> (363)..(1889)

<400> 107 <400> 107

<210> 108 <210> 108

<211> 508 <211> 508

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 108 <400> 108

<210> 109 <210> 109

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 109 <400> 109

<210> 110 <210> 110

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 110 <400> 110

<210> 111 <210> 111

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 111 <400> 111

<210> 112 <210> 112

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 112 <400> 112

<210> 113 <210> 113

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 113 <400> 113

<210> 114 <210> 114

<211> 21 <211> 21

<212> DNA <212> DNA

<213> 人工 <213> Labor

<220> <220>

<223> 結合DNA/RNA分子：合成寡核苷酸 <223> Binding DNA/RNA Molecules: Synthetic Oligonucleotides

<220> <220>

<221> 未歸類特性 <221> Uncategorized features

<222> (1)..(19) <222> (1)..(19)

<223> RNA <223> RNA

<400> 114 <400> 114

【本案指定代表圖】：第(12)圖。 [Designated representative map of this case]: Picture (12).

Claims (21)

一種癌細胞之細胞死亡誘導劑，其包含抑制GST-π之藥物、與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物作為有效成分。 A cell death inducing agent for cancer cells, which comprises a drug which inhibits GST-π and a drug which inhibits a protein which exhibits a synthetic lethality-maintaining property if it is inhibited together with GST-π as an active ingredient. 一種癌細胞之細胞增殖抑制劑，其包含抑制GST-π之藥物、與抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物作為有效成分。 A cell proliferation inhibitor for cancer cells, which comprises a drug which inhibits GST-π and a drug which inhibits the maintenance of a protein which is associated with the maintenance of lethality when it is inhibited together with GST-π as an active ingredient. 如請求項1或2之劑，其中與GST-π之抑制一併顯示出合成致死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 The agent of claim 1 or 2, wherein the above-mentioned constant maintenance-maintaining related protein exhibiting synthetic lethality together with inhibition of GST-π is selected from a cell cycle regulatory protein, an anti-apoptosis-related protein, and a PI3K signal transmission pathway. A protein in a group consisting of related proteins. 如請求項3之劑，其中與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種細胞週期調節蛋白質。 The agent of claim 3, wherein the cell cycle regulatory protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, At least one cell cycle regulatory protein of the group consisting of BRSK1, MCM8, CCNB3, MCMDC1, and MYLK. 如請求項3之劑，其中與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 The agent of claim 3, wherein the cell cycle regulatory protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from at least one of the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3 and MCMDC1. . 如請求項3之劑，其中與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 The agent according to claim 3, wherein the anti-apoptosis-related protein which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1. At least one anti-apoptosis-related protein of a group consisting of BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A. 如請求項3之劑，其中與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 The agent of claim 3, wherein the PI3K signal transmission path-related protein line which exhibits synthetic lethality together with the inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, At least one of the PI3K signaling pathway-associated proteins of the group consisting of EIF4E, ILK, MTCP1, PIK3CA, and SRF. 如請求項1或2之劑，其中上述藥物係選自由RNAi分子、核酶、反義核酸、DNA/RNA嵌合聚核苷酸及表現該等之中至少1種之載體所組成之群的物質。 The agent according to claim 1 or 2, wherein the drug is selected from the group consisting of an RNAi molecule, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and a vector expressing at least one of the vectors substance. 如請求項1或2之劑，其中上述抑制恆常性維持相關蛋白質之藥物係作用於該恆常性維持相關蛋白質之化合物。 The agent according to claim 1 or 2, wherein the drug which inhibits the constantity maintaining the related protein acts on the compound which maintains the related protein in the constantity. 如請求項1之劑，其誘導細胞凋亡。 As claimed in claim 1, it induces apoptosis. 如請求項1或2之劑，其中上述癌細胞係高度表現GST-π之癌細胞。 The agent of claim 1 or 2, wherein the cancer cell line is a cancer cell which highly expresses GST-π. 一種起因於細胞之增殖異常之疾病治療用醫藥組合物，其包含如請求項1至11中任一項之劑。 A pharmaceutical composition for treating a disease caused by abnormal proliferation of cells, which comprises the agent according to any one of claims 1 to 11. 如請求項12之醫藥組合物，其中上述疾病為癌。 The pharmaceutical composition of claim 12, wherein the disease is cancer. 如請求項13之醫藥組合物，其中上述癌係高度表現GST-π之癌。 The pharmaceutical composition according to claim 13, wherein the cancer system described above highly expresses GST-π cancer. 一種與抑制GST-π之藥物一併使用之癌細胞之細胞死亡誘導劑及/或細胞增殖抑制劑之篩選方法，其包括選出抑制若與GST-π一併被抑制則顯示出合成致死性之恆常性維持相關蛋白質的藥物。 A method for screening a cell death inducing agent and/or a cell proliferation inhibitor of a cancer cell used together with a drug for inhibiting GST-π, which comprises selecting a inhibition to exhibit a synthetic lethality if it is inhibited together with GST-π A drug that maintains a related protein. 如請求項15之篩選方法，其包括：使受檢物質接觸癌細胞之步驟；測定上述細胞中之上述恆常性維持相關蛋白質之表現量的步驟；以及選出與於受檢物質之非存在下進行測定之情形相比該表現量降低之情形時抑制上述恆常性維持相關蛋白質之藥物的步驟。 The screening method of claim 15, comprising the steps of: contacting the test substance with the cancer cell; determining the above-mentioned constant in the cell to maintain the expression amount of the related protein; and selecting the non-existing substance in the test substance The step of performing the measurement is a step of suppressing the above-described constant maintenance of the drug of the related protein as compared with the case where the amount of expression is lowered. 如請求項15之篩選方法，其中與GST-π之抑制一併顯示出合成致 死性之上述恆常性維持相關蛋白質係選自由細胞週期調節蛋白質、抗細胞凋亡相關蛋白質及PI3K訊號傳遞路徑相關蛋白質所組成之群中之蛋白質。 The screening method of claim 15, wherein the inhibition of GST-π is combined with the synthesis The above-described constant maintenance related protein of death is selected from the group consisting of a cell cycle regulatory protein, an anti-apoptosis-related protein, and a PI3K signaling pathway-related protein. 如請求項17之篩選方法，其中與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由ATM、CDC25A、p21、PRKDC、RBBP8、SKP2、MCM10、RNPC1、CCNL1、CENPH、BRSK1、MCM8、CCNB3、MCMDC1及MYLK所組成之群中之至少一種蛋白質。 The screening method according to claim 17, wherein the cell cycle regulatory protein line which exhibits synthetic lethality together with inhibition of GST-π is selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH At least one of the group consisting of BRSK1, MCM8, CCNB3, MCMDC1, and MYLK. 如請求項17之篩選方法，其中與GST-π之抑制一併顯示出合成致死性之上述細胞週期調節蛋白質係選自由p21、RNPC1、CCNL1、MCM8、CCNB3及MCMDC1所組成之群中之至少一種蛋白質。 The screening method according to claim 17, wherein the cell cycle regulatory protein line which exhibits synthetic lethality together with inhibition of GST-π is at least one selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3 and MCMDC1. protein. 如請求項17之篩選方法，其中與GST-π之抑制一併顯示出合成致死性之上述抗細胞凋亡相關蛋白質係選自由AATF、ALOX12、ANXA1、ANXA4、API5、ATF5、AVEN、AZU1、BAG1、BCL2L1、BFAR、CFLAR、IL2、MALT1、MCL1、MKL1、MPO、MTL5、MYBL2及MYO18A所組成之群中之至少一種抗細胞凋亡相關蛋白質。 The screening method according to claim 17, wherein the anti-apoptosis-related protein line which exhibits synthetic lethality together with the inhibition of GST-π is selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1. At least one anti-apoptosis-related protein of a group consisting of BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A. 如請求項17之篩選方法，其中與GST-π之抑制一併顯示出合成致死性之上述PI3K訊號傳遞路徑相關蛋白質係選自由MTOR、IRAK1、IRS1、MYD88、NFKB1、PIK3CG、RAC1、AKT3、EIF4B、EIF4E、ILK、MTCP1、PIK3CA及SRF所組成之群中之至少一種PI3K訊號傳遞路徑相關蛋白質。 The screening method according to claim 17, wherein the PI3K signal transmission path-related protein line which exhibits synthetic lethality together with the inhibition of GST-π is selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B. At least one of the PI3K signaling pathway-associated proteins of the group consisting of EIF4E, ILK, MTCP1, PIK3CA, and SRF.
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