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WO2023043261A1 - Composition pharmaceutique pour améliorer l'effet anticancéreux d'un médicament anticancéreux - Google Patents

Composition pharmaceutique pour améliorer l'effet anticancéreux d'un médicament anticancéreux Download PDF

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Publication number
WO2023043261A1
WO2023043261A1 PCT/KR2022/013879 KR2022013879W WO2023043261A1 WO 2023043261 A1 WO2023043261 A1 WO 2023043261A1 KR 2022013879 W KR2022013879 W KR 2022013879W WO 2023043261 A1 WO2023043261 A1 WO 2023043261A1
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cancer
aqtgtgkt
group
anticancer
pharmaceutical composition
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Korean (ko)
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전도용
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L Base Co Ltd
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L Base Co Ltd
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Priority claimed from KR1020220116621A external-priority patent/KR102786112B1/ko
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a compound that can exhibit a synergistic effect through combined administration with an anticancer agent such as a targeted anticancer agent and a chemotherapy agent in cancer treatment, and a pharmaceutical composition comprising a combination of the compound and an anticancer agent.
  • an anticancer agent such as a targeted anticancer agent and a chemotherapy agent in cancer treatment
  • a pharmaceutical composition comprising a combination of the compound and an anticancer agent.
  • cancer is still a serious disease that competes for the first and second place among the causes of death in Korea.
  • Most of the currently used anticancer drugs are chemotherapy, which is pointed out as a problem in cancer treatment because pharmacological actions vary depending on the type of cancer and various side effects due to toxicity appear. Therefore, in order to overcome the limitations of these chemotherapeutic systems, it is continuously necessary to develop targeted therapies with clear anticancer mechanisms.
  • the combination therapy for cancer treatment has the advantage of attacking cancer cells through multiple means, it is widely used in cancer treatment.
  • Korean Patent Publication No. 10-2014-0097607 a pharmaceutical composition for combination administration for cancer treatment has initiated.
  • Combination therapy can minimize the toxicity and side effects of the anticancer agent by reducing the amount of the anticancer agent administered while enhancing the efficacy of the anticancer agent, and is useful even when resistance to the anticancer agent is exhibited.
  • many effective combination therapies have been identified over the past few decades, developing effective combination therapies is important in light of the continuing increase in the number of people dying of cancer each year.
  • the present invention has been made to solve the problems of the prior art as described above, and the anticancer active peptide AQTGTGKT (alanine-glutamine-threonine-glycine-threonine-glycine-lysine-threonine) or its amidated analog compound is
  • the present invention was completed by confirming that a significant synergistic effect in anticancer activity was observed when administered in combination with an anticancer agent.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the compound according to the present invention and an anticancer agent as active ingredients.
  • Another object of the present invention is to provide a kit for preventing or treating cancer, comprising the compound according to the present invention and an anticancer agent as active ingredients.
  • Another object of the present invention is to provide a pharmaceutical composition for enhancing the anti-cancer effect of an anti-cancer agent.
  • the present invention is (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a pharmaceutical composition for preventing or treating cancer comprising an anticancer agent as an active ingredient:
  • the analog is a compound represented by the general formula X-AQTGTGKT, and the X may be a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof, but is not limited thereto:
  • R 1 is hydrogen, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted C 1 to C 5 alkyl group.
  • R 1 may be represented by any one of Formulas 2 to 4, but is not limited thereto:
  • R 2 and R 4 are each independently hydrogen, a C 1 to C 5 alkyl group, or a phenyl group;
  • R 3 is hydrogen, a C 1 to C 5 alkyl group, a phenyl group, or a C 1 to C 3 alkoxy group.
  • R 6 and R 7 are each independently hydrogen or a C 1 to C 3 alkyl group.
  • the anticancer agent may be at least one selected from the group consisting of a target anticancer agent and a chemotherapy agent, but is not limited thereto.
  • the target anti-cancer agent is a tyrosine kinase inhibitor, a PARP inhibitor, an angiogenesis inhibitor, a CDK4/6 inhibitor (cyclin-dependent kinases 4/6 inhibitor), hormone therapy drugs, and antibody- It may be one or more selected from the group consisting of drug conjugates (antibody-drug conjugates), but is not limited thereto.
  • the tyrosine kinase inhibitor is epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), B-Raf Proto-Oncogene (BRAF), HER2 ( target for one or more selected from the group consisting of human epidermal growth factor receptor 2), RET (Ret Proto-Oncogene), NTRK1 (Neurotrophic Receptor Tyrosine Kinase 1), MET (Mesenchymal-Epithelial Transition factor), and NRG1 (Neuregulin 1) It may be a drug, but is not limited thereto.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • ROS1 ROS Proto-Oncogene 1
  • BRAF B-Raf Proto-Oncogene
  • HER2 target for one or more selected from the group consisting of human epidermal growth factor receptor
  • the tyrosine kinase inhibitor is Osimertinib, Afatinib, Cruatinib, Dasatinib, Dacomitinib, Elo Erlotinib, Gefitinib, Lapatinib, Neratinib, Vandetanib, Icotinib, Varitinib, Tesevatinib, Canertinib, Naquotinib, Pelitinib, Poziotinib, Rociletinib, Nazartinib, Allitinib (ALS-1306), Pyrotinib, Tyrphostin, Crizotinib, Ceritinib, Entrectinib, Dabrafenib, Trametinib, Alectinib (Alectinib), lorlatinib, Larotectinib, Lazertinib, Olmutinib, AG 1478, CUDC-101, MTKi-3
  • the PARP inhibitor is selected from the group consisting of Olaparib, Rucaparib, Talazoparib, Veliparib, and Niraparib It may be one or more, but is not limited thereto.
  • the CDK4/6 inhibitor is 1 selected from the group consisting of Trilaciclib, Palbociclib, Ribociclib, and Abemaciclib. It may be more than one species, but is not limited thereto.
  • the hormone therapy agent is Tamoxifen, Toremifene, Fulvestrant, Goserelin, Leuprolide, Anastrozole , Letrozole, and exemestane, but may be one or more selected from the group consisting of, but is not limited thereto.
  • the antibody-drug conjugate may be at least one selected from the group consisting of Sacituzumab govitecan and Ladiratuzumab, but is not limited thereto.
  • the target anticancer agent may be at least one selected from the group consisting of Daratumumab, Trastuzumab, and Rituximab, but is not limited thereto. .
  • the chemotherapeutic agent is Alimta, Oxaliplatin, Pemetrexed, Cisplatin, Gemcitabine, Carboplatin, Fluoro It may be at least one selected from the group consisting of uracil (5-FU), cyclophosphamide, paclitaxel, vincristine, etoposide, and doxorubicin, but is limited thereto It doesn't work.
  • the oligopeptide or an analog thereof may enhance the anticancer effect of the anticancer agent and reduce side effects, but is not limited thereto.
  • the composition comprises the oligopeptide or analog thereof;
  • the anticancer agent may be in the form of a mixed agent, but is not limited thereto.
  • the composition comprises the oligopeptide or analog thereof;
  • the anticancer agent may be each formulated and administered simultaneously, separately, or sequentially, but is not limited thereto.
  • the anticancer agent may be included in a concentration of 0.01 to 10 ⁇ M compared to the total composition, but is not limited thereto.
  • the oligopeptide or analog thereof may be included in a concentration of 1 to 50 ⁇ M relative to the total composition, but is not limited thereto.
  • the anticancer agent the oligopeptide or analog thereof may be included in a molarity ratio of 1:1 to 500, but is not limited thereto.
  • the pharmaceutical composition comprises the oligopeptide or an analog thereof; targeted anti-cancer agents; And may include all of the chemotherapeutic agent, but is not limited thereto.
  • the cancer is squamous cell carcinoma, lung cancer, adenocarcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, perianal cancer, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, appendix Thyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, blood cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver tumor, breast cancer, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, It may be any one or more selected from the group consisting of kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, and brain cancer, but is not limited thereto.
  • the present invention provides a kit for preventing or treating cancer comprising the composition according to the present invention:
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a pharmaceutical composition for enhancing the anti-cancer effect of an anti-cancer agent comprising an anti-cancer agent as an active ingredient.
  • the analog is a compound represented by the general formula X-AQTGTGKT, and the X may be a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof, but is not limited thereto:
  • R 1 is hydrogen, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted C 1 to C 5 alkyl group.
  • R 1 may be represented by any one of Formulas 2 to 4, but is not limited thereto:
  • R 2 and R 4 are each independently hydrogen, a C 1 to C 5 alkyl group, or a phenyl group;
  • R 3 is hydrogen, a C 1 to C 5 alkyl group, a phenyl group, or a C 1 to C 3 alkoxy group.
  • R 6 and R 7 are each independently hydrogen or a C 1 to C 3 alkyl group.
  • the composition may be administered simultaneously with, separately from, or sequentially with the anticancer agent, but is not limited thereto.
  • the composition is used for squamous cell carcinoma, lung cancer, adenocarcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, perianal cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer , adrenal cancer, soft tissue sarcoma, urethral cancer, blood cancer, liver cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver tumor, breast cancer, colon cancer, colon cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney It may be for enhancing the anticancer effect of the anticancer agent for one or more cancers selected from the group consisting of cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, and brain cancer, but is not limited thereto.
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; and (ii) administering a composition containing an anticancer agent as an active ingredient to a subject in need thereof, providing a method for preventing or treating cancer.
  • the oligopeptide or an analog thereof; and anticancer agents may be administered in effective amounts, respectively, but are not limited thereto.
  • the present invention provides a method for enhancing the anticancer effect of an anticancer agent, comprising administering the oligopeptide or an analog thereof to a subject in need thereof.
  • the oligopeptide or analog thereof may be administered in an effective amount, but is not limited thereto.
  • the present invention provides the use of the oligopeptide or its analogue for the preparation of an anti-cancer effect enhancing agent of an anti-cancer drug.
  • the present invention provides a use of enhancing the anticancer effect of the oligopeptide or its analogue as an anticancer agent.
  • the use of enhancing the anticancer effect of the anticancer agent includes the use of suppressing the side effects of the anticancer agent.
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a use for the manufacture of a drug for the treatment of cancer of the composition containing the anticancer agent as an active ingredient.
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a use for preventing or treating cancer of a composition comprising an anticancer agent as an active ingredient.
  • the present invention relates to a pharmaceutical composition for preventing/treating cancer, a composition for enhancing the anticancer effect of an anticancer agent, and the like, wherein the composition is an oligopeptide AQTGTGKT and its analog based on an autophagy mechanism involved in the resistance of existing anticancer agents as a tumor promoter. compound as an active ingredient.
  • the oligopeptide and its analogues according to the present invention selectively bind to the protein target involved in the upper stage of autophagy only in the advanced state of cancer and over-activate autophagy, specifically targeting cancer cells without affecting normal cells. Since it can be targeted, it is possible to maximize the inhibitory effect on cancer cell proliferation while minimizing the side effects of the existing anticancer drug alone treatment effect on anticancer drug-resistant patients.
  • oligopeptide AQTGTGKT and its analog compounds when administered in combination with conventional anticancer drugs, they exhibit an increased anticancer effect, and even a low concentration of the drug exhibits a significantly superior anticancer effect of suppressing cancer cell proliferation, so it is not effective in normal tissues. It can minimize side effects such as functional and activity damage, bone marrow function decline, gastrointestinal disorder, alopecia, and anticancer drug resistance.
  • oligopeptides are expected to be used in combination with anticancer drugs for various cancer types because they have a small molecular weight compared to antibodies, so there is less concern about immune reactions and they are easy to penetrate into tissues.
  • Figure 1a shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib (Osimertinib) in lung cancer cell line H1975 by MTT assay ( * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001; the same below).
  • Figure 1b shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 4-PhPh-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1c shows the result of analyzing the cell activity inhibition effect according to the combined treatment of Ac-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1d shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 4-MeOPh-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1e shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 2-PhPh-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1f shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound Ph-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1g shows the results of analyzing the cell activity inhibition effect according to the combined treatment of the compound Naphtyl-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H1975 by MTT assay.
  • Figure 1h shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib in the lung cancer cell line H1975/OR by MTT assay.
  • Figure 2a shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 4-PhPh-AQTGTGKT and Alimta according to the present invention in lung cancer cell line H1975 by MTT assay.
  • Figure 2b shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and Alimta in the lung cancer cell line H1975/OR by MTT assay.
  • Figure 2c shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 2-PhPh-AQTGTGKT according to the present invention and Alimta in lung cancer cell line H1975 by MTT assay.
  • Figure 2d shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound Ph-AQTGTGKT according to the present invention and Alimta in lung cancer cell line H1975 by MTT assay.
  • Figure 2e shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound Naphtyl-AQTGTGKT and Alimta according to the present invention in lung cancer cell line H1975 by MTT assay.
  • Figure 3 shows the results of analyzing the cell activity inhibition effect according to the triple combination treatment of the compound 3-PhPh-AQTGTGKT according to the present invention, osimertinib, and Alimta in lung cancer cell line H1975 by MTT assay.
  • Figure 4a shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H820 by MTT assay.
  • Figure 4b shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib in lung cancer cell line H820 by MTT assay.
  • Figure 5 shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib in the lung cancer cell line PC9/OR by MTT assay.
  • Figure 6a shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound AQTGTGKT according to the present invention and up parip (Olaparib) in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6b shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and parip up in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6c shows the results of analyzing the cell activity inhibition effect according to the combined treatment of the compound 4-PhPh-AQTGTGKT according to the present invention and up parip in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6d shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound Acyl-PhPh-AQTGTGKT and parip according to the present invention in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6e shows the results of analyzing the cell activity inhibition effect according to the combined treatment of the compound 2-PhPh-AQTGTGKT according to the present invention and parip up in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6f shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound Ph-AQTGTGKT according to the present invention and parip up in breast cancer cell line HCC1937 by MTT assay.
  • Figure 6g shows the results of analyzing the cell activity inhibitory effect according to the combined treatment of the compound Naphtyl-AQTGTGKT and up parip according to the present invention in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7a shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 4-MeOph-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7b shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7c shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound 4-PhPh-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7d shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound Acyl-PhPh-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7e shows the result of analyzing the cell activity inhibitory effect according to the combined treatment of the compound 2-PhPh-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • 7f shows the result of analyzing the cell activity inhibitory effect of the combined treatment of the compound Ph-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 7g shows the result of analyzing the cell activity inhibition effect according to the combined treatment of the compound Naphtyl-PhPh-AQTGTGKT according to the present invention and cisplatin in breast cancer cell line HCC1937 by MTT assay.
  • Figure 8a shows the results of comparative analysis of the cell growth inhibitory effect according to the combination treatment time point in order to search for the optimal combination therapy of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib in cancer cells.
  • Figure 8b shows the results of comparative analysis of the cell growth inhibitory effect according to the combination treatment period for specific exploration of the optimal combination therapy of the compound 3-PhPh-AQTGTGKT and osimertinib according to the present invention in the lung cancer cell line PC9 / OR.
  • Figure 9a is a view showing the results of comparative analysis of the tumor growth inhibitory effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib after inoculating the lung cancer cell line H820 into nude mice to form tumors.
  • Figure 9b is a view showing the results of comparative analysis of the tumor growth inhibitory effect according to the combined treatment of the compound 3-PhPh-AQTGTGKT according to the present invention and osimertinib after tumors were formed by inoculating the lung cancer cell line H1975 into nude mice.
  • FIG. 10 is a diagram showing the results of analyzing the degree of tumor growth according to single or combined administration of Lazertinib and the compound according to the present invention (3-PhPh-AQTGTGKT) in a PDX model transplanted with tumor tissue of a lung cancer patient.
  • FIG. 11 is a diagram showing the results of analyzing the degree of tumor growth according to single or combined administration of osimertinib and the compound (3-PhPh-AQTGTGKT) according to the present invention in a PDX model transplanted with tumor tissue of a lung cancer patient.
  • FIG. 12 shows tumor growth results according to the combined administration of the compound (3-PhPh-AQTGTGKT) according to the present invention after resistance to osimertinib was developed in a lung cancer animal model prepared using the H1975 cell line.
  • FIG. 13 shows tumor growth results according to the combined administration of the compound (3-PhPh-AQTGTGKT) according to the present invention before resistance to osimertinib was expressed in a lung cancer animal model prepared using the H1975 cell line.
  • FIG. 14a to 14c show the administration of AQTGTGKT (FIG. 14a), 3-PhPh-AQTGTGKT (FIG. 14b), and Ph-AQTGTGKT (FIG. 14c), which are compounds according to the present invention, in breast cancer animal models prepared using the HCC1806 cell line; This is the result of analyzing tumor growth following co-administration with cisplatin.
  • FIG. 16 to 22 are diagrams showing the results of UPLC-MS (top) and 1 H NMR (bottom) for identifying the compound according to the present invention and confirming the structure of the compound.
  • FIG. 16 is 4-PhPh-AQTGTGKT
  • FIG. 17 is Ac-AQTGTGKT
  • FIG. 18 is 3-PhPh-AQTGTGKT
  • FIG. 19 is 4-MeOPh-AQTGTGKT
  • FIG. 20 is 2-PhPh-AQTGTGKT
  • FIG. 21 is Ph-AQTGTGKT
  • FIG. 22 is Naphthyl-AQTGTGKT. it is shown
  • the inventors of the present invention completed the present invention by confirming that the oligopeptide AQTGTGKT or its amidation analog exhibits a more improved anticancer effect when used in combination with conventional anticancer drugs in various cancer cell lines.
  • the anti-cancer effect significantly increased when a target anti-cancer agent and / or a chemo-anticancer agent in various lung cancer cell lines were treated in combination with the compound according to the present invention, compared to the case of treatment alone ( see Example 1).
  • osimertinib was treated alone and then 3-PhPh-AQTGTGKT was added to the combination treatment. It was found that when osimertinib and 3-PhPh-AQTGTGKT were treated in combination and then osimertinib was treated alone, a much improved anticancer effect was exhibited (see Example 3.1).
  • osimertinib and 3-PhPh-AQTGTGKT were treated in combination and then osimertinib It was found that the case of continuous treatment with osimertinib and 3-PhPh-AQTGTGKT showed a more improved anticancer effect than the case of treatment alone (see Example 3.2).
  • the compound and the anticancer agent were administered alone, respectively. It was confirmed that there was a more elevated tumor growth inhibitory effect when these were administered in combination than in one case (see Example 4).
  • the effect of the combined administration of osimertinib and 3-PhPh-AQTGTGKT before and after resistance to anticancer drugs was confirmed using a xenograft lung cancer animal model made with the H1975 lung cancer cell line was confirmed. , It was confirmed that there was a more enhanced tumor growth inhibitory effect when the compound and the anticancer agent were administered in combination, both before and after resistance was developed, than when the compound and the anticancer agent were administered alone (see Example 6).
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a pharmaceutical composition for preventing or treating cancer comprising an anticancer agent as an active ingredient.
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a kit for preventing or treating cancer, including an anticancer agent.
  • the present invention provides (i) an oligopeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an analog thereof; And (ii) it provides a pharmaceutical composition for enhancing the anti-cancer effect of an anti-cancer agent comprising an anti-cancer agent as an active ingredient.
  • the present invention provides a pharmaceutical composition for suppressing the side effects of anticancer drugs comprising the compound represented by the above general formula as an active ingredient. Suppression of the side effects of the anticancer agent includes inhibition of resistance to the anticancer agent.
  • the present invention provides a pharmaceutical composition for concomitant administration of an anticancer agent comprising the compound represented by the general formula as an active ingredient.
  • the analog is a compound represented by the general formula X-AQTGTGKT, and X may be a compound represented by the following formula 1, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted C 1 to C 5 alkyl group.
  • R 1 may be represented by any one of Formulas 2 to 4 below:
  • R 2 and R 4 are each independently hydrogen, a C 1 to C 5 alkyl group, or a phenyl group;
  • R 3 is hydrogen, a C 1 to C 5 alkyl group, a phenyl group, or a C 1 to C 3 alkoxy group.
  • R 6 and R 7 are each independently hydrogen or a C 1 to C 3 alkyl group.
  • the compound according to the present invention may be a compound represented by the following general formula or a pharmaceutically acceptable salt thereof:
  • A is alanine
  • Q is glutamine
  • T is threonine
  • G is glycine
  • K is lysine
  • X is not present
  • the phosphorus compound may be referred to herein as “3-PhPh-AQTGTGKT”.
  • the names of the compounds according to the present invention are listed in Table 1.
  • oligopeptides and analogs thereof according to the present invention may be simply referred to as "compounds”.
  • oligopeptide refers to a linear molecule formed by linking amino acid residues to each other by a peptide bond.
  • the amidated oligopeptide of the present invention can be prepared according to chemical synthesis methods (eg, solid-phase synthesis techniques) known in the art together with molecular and biological methods (Merrifield, J. Amer Chem Soc 85: 2149-54 (1963) Stewart, et al., Solid Phase Peptide Synthesis, 2nd. ed., Pierce Chem.
  • the scope of the compounds according to the present invention may also include pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable means that the benefit/risk ratio is reasonable without excessive toxicity, irritation, allergic reaction, or other problems or complications, so that it is suitable for use in contact with the tissue of a subject (eg, human). It means a compound that is suitable and within the scope of sound medical judgment.
  • the pharmaceutically acceptable salt includes, for example, an acid addition salt formed with a pharmaceutically acceptable free acid and a pharmaceutically acceptable metal salt.
  • suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesul
  • phonic acid formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid.
  • Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can also be prepared by heating equimolar amounts of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or suction filtering the precipitated salt.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
  • the alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable for pharmaceutical purposes to prepare a sodium, potassium or calcium salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • a suitable silver salt eg, silver nitrate
  • the scope of the compound of the present invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.
  • the compound may have a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures and cis- or trans-isomers. All these isomeric forms are contemplated.
  • the scope of the compounds according to the present invention may include biological functional equivalents having mutations in the amino acid sequence that exhibit equivalent biological activity to the compounds of the present invention. Variations of such amino acid sequences can be made based on the relative similarity of amino acid side chain substituents, such as hydrophobicity, hydrophilicity, charge and size. Analysis of the size, shape and type of amino acid side chain substituents revealed that alanine and glycine have similar sizes; Lysine is a positively charged residue; It can be seen that glutamine and threonine are not charged. Accordingly, based on these considerations, alanine and glycine; And glutamine and threonine can be said to be biologically functional equivalents. Unless otherwise stated, the amino acid sequence disclosed herein is in principle written in order from the N-terminus to the C-terminus.
  • each amino acid is given a hydrophobicity index according to its hydrophobicity and charge as follows: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); Tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamic acid (-3.5); glutamine (-3.5); aspartic acid (-3.5); asparagine (-3.5); Lysine (-3.9); and arginine (-4.5).
  • the hydrophobic amino acid index is very important in conferring the interactive biological function of proteins. It is a known fact that amino acids having similar hydrophobicity indexes should be substituted to retain similar biological activities. When a mutation is introduced with reference to the hydrophobicity index, substitution is made between amino acids exhibiting a difference in hydrophobicity index, preferably within ⁇ 2, more preferably within ⁇ 1, and even more preferably within ⁇ 0.5.
  • hydrophilicity value When a mutation is introduced by referring to the hydrophilicity value, substitution is made between amino acids showing a difference in hydrophilicity value, preferably within ⁇ 2, more preferably within ⁇ 1, even more preferably within ⁇ 0.5.
  • Amino acid exchanges in proteins that do not entirely alter the activity of the molecule are known in the art (H. Neurath, R.L. Hill, The Proteins, Academic Press, New York, 1979).
  • the most commonly occurring exchanges are amino acid residues Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/ Exchange between Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly.
  • the oligopeptide according to the present invention is not limited to its amino acid sequence (AQTGTGKT), but is interpreted to include a sequence exhibiting substantial identity therewith.
  • the above substantial identity is at least when the sequence of the present invention and any other sequence described above are aligned so as to correspond as much as possible, and the aligned sequence is analyzed using an algorithm commonly used in the art. It means a sequence exhibiting 62.5% homology, more preferably 75% or more homology, and most preferably 87.5% or more homology. Alignment methods for sequence comparison are known in the art.
  • the term "combined administration" can be achieved by administering the individual components of a treatment regimen simultaneously, sequentially, or separately.
  • a combination treatment effect is obtained by administering two or more drugs simultaneously or sequentially, or by alternately administering them at regular or unspecified intervals.
  • efficacy measured by time to disease progression or survival can be defined as being therapeutically superior to and capable of providing a synergistic effect over the efficacy obtainable by administering one or the other of the components of a combination therapy at conventional doses.
  • anti-cancer agent is used as a generic term for substances used for the treatment of malignant tumors.
  • Most anticancer drugs are drugs that inhibit the synthesis of nucleic acids or exhibit anticancer activity by intervening in various metabolic pathways of cancer cells.
  • Anticancer drugs currently used for cancer treatment are alkylating agents, antimetabolites, antibiotics, and mitotic inhibitors (vinca alkaloids) depending on their biochemical mechanism of action.
  • Hormonal agents, and other six categories, but anticancer agents according to the present invention may not be included in the above categories.
  • the anticancer agent may be at least one selected from the group consisting of a target anticancer agent and a chemotherapy agent, but is not limited thereto.
  • the composition of the present invention may be administered together with a targeted anticancer agent.
  • targeted anti-cancer agent refers to an agent that exhibits an anti-cancer effect by interfering with molecular activity involved in the growth and development of cancer by targeting a protein or gene that is specifically changed in cancer cells or cancer tissues.
  • the target anticancer agent is a tyrosine kinase inhibitor (TKI), PARP inhibitor (poly-ADP ribose polymerase inhibitors), angiogenesis inhibitor, CDK4/6 inhibitor (cyclin-dependent kinases 4/6 inhibitor), hormone It may be one or more selected from the group consisting of hormonal therapy drugs and antibody-drug conjugates, but is not limited thereto.
  • the target anti-cancer agent according to the present invention may be a monoclonal antibody anti-cancer agent, but is not limited thereto.
  • the tyrosine kinase inhibitor is epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), B-Raf Proto-Oncogene (BRAF), human epidermal growth factor receptor 2 (HER2) , RET (Ret Proto-Oncogene), NTRK1 (Neurotrophic Receptor Tyrosine Kinase 1), MET (Mesenchymal-Epithelial Transition factor), and NRG1 (Neuregulin 1).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • ROS1 ROS Proto-Oncogene 1
  • BRAF B-Raf Proto-Oncogene
  • HER2 human epidermal growth factor receptor 2
  • RET Ret Proto-Oncogene
  • NTRK1 Neurotrophic Receptor Tyrosine Kinase 1
  • Limited examples include Osimertinib, Afatinib, Cruatinib, Dasatinib, Dacomitinib, Erlotinib, Gefitinib ), Lapatinib, Neratinib, Vandetanib, Icotinib, Varitinib, Tesevatinib, Canertinib, Nacuotinib (Naquotinib), Pelitinib, Poziotinib, Rociletinib, Nazartinib, Allitinib (ALS-1306), Pyrotinib, Tyrphostin ( Tyrphostin), Crizotinib, Ceritinib, Entrectinib, Dabrafenib, Trametinib, Alectinib, Lorlatinib Larotectinib, Lazertinib, Olmutinib, AG 1478, CUDC- 101, MTKi-327 (JNJ-26483327), CL
  • the PARP inhibitor may be one or more selected from the group consisting of Olaparib, Rucaparib, Talazoparib, Veliparib, and Niraparib, but It is not limited.
  • the CDK4/6 inhibitor may be at least one selected from the group consisting of Trilaciclib, Palbociclib, Ribociclib, and Abemaciclib, but is limited thereto. it is not going to be
  • hormone therapy agent is Tamoxifen, Toremifene, Fulvestrant, Goserelin, Leuprolide, Anastrozole, Letrozole, And exemestane (Exemestane) may be one or more selected from the group consisting of, but is not limited thereto.
  • the targeted anti-cancer agent according to the present invention may be antibody-drug conjugates (ADCs).
  • ADC is made by covalently conjugating an antibody that binds to a specific target antigen on the surface of cancer cells and a drug having a strong apoptotic function, and has the antibody's target selectivity and the drug's strong killing activity. It is an anti-cancer drug with high therapeutic effect and low side effects by selectively acting on cancer cells only.
  • the ADC may be selected from Sacituzumab govitecan, Ladiratuzumab, etc., but is not limited thereto.
  • target anticancer agent according to the present invention may be selected from Daratumumab, Trastuzumab, and Rituximab, but is not limited thereto.
  • composition of the present invention may be administered together with a chemotherapy agent.
  • a chemotherapy agent refers to a first-generation anticancer agent that is also referred to as “cytotoxic anticancer agent” or “chemical anticancer agent”.
  • Non-limiting examples of the chemotherapy include Alimta, Oxaliplatin, Pemetrexed, Cisplatin, Gemcitabine, Carboplatin, Fluorouracil (5-FU ), Cyclophosphamide, Paclitaxel, Vincristine, Etoposide, Doxorubicin, and the like.
  • the composition (or active ingredients thereof) according to the present invention can enhance the anti-cancer effect of anti-cancer agents and reduce side effects. This is because the dosage of anticancer drugs having side effects can be minimized by appropriate combination therapy.
  • enhancing the anticancer effect refers to all effects that can consequently enhance the function of an anticancer agent, and enhancing the anticancer effect of an anticancer agent, such as suppression of tumor growth, inhibition of tumor metastasis, and inhibition of tumor recurrence, is Of course, it is a concept that includes everything from suppressing the formation of resistance or resistance of cancer cells to anticancer agents to consequently enhancing anticancer effects.
  • the oligopeptide and its analogue according to the present invention can be used as a compound for co-administration of a known anticancer agent for the purpose of enhancing anticancer effect. That is, in the present invention, the oligopeptide and its analog are used for co-administration with an anticancer agent, and can enhance the anticancer effect of the anticancer agent.
  • the oligopeptide or its analog may be administered simultaneously with the anticancer agent (simultaneously), separately (separately), or sequentially (sequentially), and even when administered sequentially with the anticancer agent, the order of administration is not limited. , Depending on the type of cancer, the type of anticancer agent, and the condition of the patient, the dosage regimen may be appropriately adjusted.
  • the cancer cell growth inhibitory effect was the highest when the compound according to the present invention and osimertinib were simultaneously treated in the initial stage of treatment. Therefore, the compound may be administered before or simultaneously with the anticancer agent.
  • the anticancer effect is even better when compared to the case where the anticancer agent is treated alone after the combination. Therefore, for the purpose of maximizing the anticancer effect, it is preferable to continuously use the compound of the present invention in combination with an anticancer agent.
  • oligopeptide or analog thereof according to the present invention may be administered simultaneously with, separately from, or sequentially with the anticancer agent or other anticancer agent before or after resistance to the anticancer agent is expressed in a subject.
  • the content of the oligopeptide or its analogue, or anticancer agent in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progress of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight based on the total weight of the composition, Or it may be 0.001 to 50% by weight, but is not limited thereto.
  • the content ratio is a value based on the dry amount after removing the solvent.
  • the anticancer agent is 0.1 to 10 ⁇ M, 0.1 to 9 ⁇ M, 0.1 to 8 ⁇ M, 0.1 to 7 ⁇ M, 0.1 to 6 ⁇ M, 0.1 to 5 ⁇ M, 0.1 to 4 ⁇ M, 0.1 to 3 ⁇ M relative to the total composition , 0.1 to 2 ⁇ M, or may be included at a concentration of 0.1 to 1 ⁇ M, but is not limited thereto. In other words, when the composition is administered to a subject, the anticancer agent may be administered at a concentration of 0.1 to 10 ⁇ M.
  • the oligopeptide or its analog is 1 to 50 ⁇ M, 1 to 40 ⁇ M, 1 to 30 ⁇ M, 1 to 20 ⁇ M, 1 to 15 ⁇ M, 1 to 12 ⁇ M, 1 to 10 ⁇ M relative to the total composition , 1 to 9 ⁇ M, 1 to 8 ⁇ M, 1 to 7 ⁇ M, 1 to 6 ⁇ M, 1 to 5 ⁇ M, 1 to 4 ⁇ M, 1 to 3 ⁇ M, 1 to 2 ⁇ M, 2 to 12 ⁇ M, or 2 to 11 It may be included at a concentration of ⁇ M, but is not limited thereto. In other words, when the composition is administered to a subject, the oligopeptide or analog thereof may be administered at a concentration of 0.1 to 10 ⁇ M.
  • composition according to the present invention may include the oligopeptide or an analog thereof; and the anticancer agent in the form of a mixed agent, wherein the oligopeptide or an analog thereof; And it may be a form for simultaneous (simultaneous) administration of the anticancer agent.
  • the composition according to the present invention may include the oligopeptide or an analog thereof; And the anticancer agent may be formulated and administered simultaneously (simultaneously), separately (separately), or sequentially (sequentially).
  • the composition is a first pharmaceutical composition comprising a pharmaceutically effective amount of the oligopeptide or its analog as an active ingredient; And it may be a pharmaceutical composition for combined administration for simultaneous or sequential administration, including a second pharmaceutical composition containing a pharmaceutically effective amount of the anticancer agent as an active ingredient.
  • the administration order is not limited, and the administration regimen may be appropriately adjusted according to the condition of the patient.
  • the pharmaceutical composition is a pharmaceutical composition for combined administration for sequential administration
  • the oligopeptide or analog thereof (“first component”) is first administered, and then the anticancer agent (“second component”) is administered.
  • first component the oligopeptide or analog thereof
  • second component the anticancer agent
  • the anticancer agent is a tyrosine kinase inhibitor, more preferably, Osimertinib, and the oligopeptide or analog thereof according to the present invention is a compound represented by the general formula X-AQTGTGKT, wherein X is present don't; or
  • the anticancer agent is a PARP inhibitor, more preferably Olaparib, and the oligopeptide or analog thereof according to the present invention is a compound represented by the general formula X-AQTGTGKT, wherein X is absent; or
  • the anticancer agent is cisplatin
  • the oligopeptide or analog thereof according to the present invention is a compound represented by the general formula X-AQTGTGKT, wherein X is absent; or
  • the anticancer agent is Alimta
  • the oligopeptide or analog thereof according to the present invention is a compound represented by the general formula X-AQTGTGKT, wherein X is
  • the anticancer agent is Lazertinib
  • the oligopeptide or analog thereof according to the present invention is a compound represented by the general formula X-AQTGTGKT, wherein X is It may be, but is not limited thereto.
  • the anticancer agent and the oligopeptide or its analog are 1: 1 to 500, 1: 1 to 400, 1: 1 to 300, 1: 1 to 200, 1: 1 to 180, 1: 1 to 150, 1: 1 to 130, 1:1 to 120, 1:1 to 110, 1:1 to 100, 1:1 to 90, 1:1 to 80, 1:1 to 70, 1:1 to 60, 1:1 to 50 , 1:1 to 40, 1:1 to 30, 1:1 to 20, 1:1 to 10, 1:1 to 9, 1:1 to 8, 1:1 to 7, 1:1 to 6, 1 : It may be included in a molarity ratio of 1 to 5, 1: 1 to 4, 1: 1 to 3, or 1: 1 to 2.
  • the present invention relates to an oligopeptide or an analog thereof according to the present invention; targeted anti-cancer agents; And it provides a pharmaceutical composition for preventing or treating cancer, including both chemotherapy.
  • the inventors of the present invention have shown that when the oligopeptide or its analogue according to the present invention is used in triple combination with a target anticancer agent and a chemotherapeutic agent, the anticancer effect is better than that of the compound according to the present invention alone, It was confirmed that the anticancer effect was significantly increased compared to the combined use of the target anticancer agent and the chemotherapy agent. Therefore, when the oligopeptide or its analogue according to the present invention is used in triplicate with a target anticancer agent and a chemotherapy agent, more excellent cancer prevention and treatment effects can be achieved.
  • the molar concentration ratio of the chemical anticancer agent:target anticancer agent:the oligopeptide or analog thereof may be 1:5 to 50:5 to 200.
  • the chemical anticancer agent: the target anticancer agent: the oligopeptide or its analogue may be included in a molar concentration ratio of 1:5 to 50:5 to 200, but is not limited thereto.
  • the chemical anticancer agent: the target anticancer agent: the oligopeptide or an analog thereof is 1: 5 to 50: 5 to 150, 1: 5 to 50: 5 to 100, 1: 5 to 40: 5 to 200, 1:5 to 40:5 to 150, 1:5 to 30:5 to 150, 1:5 to 30:5 to 100, 1:5 to 30:5 to 80, 1:5 to 30:5 to 60, 1:10 to 30:20 to 150, 1:10 to 30:30 to 100, 1:10 to 30:30 to 80, 1:10 to 30:30 to 70, 1:15 to 30:40 to It may be included in a molar concentration ratio of 100, 1:15 to 25:30 to 80, 1:15 to 25:30 to 60, or 1:15 to 25:40 to 60, but is not limited thereto.
  • the oligopeptide or analog thereof according to the present invention can be used for preventing and/or treating cancer.
  • cancer is characterized by uncontrolled cell growth, which results in the formation of a cell mass called a tumor, infiltrating surrounding tissues and, in severe cases, metastasizing to other organs in the body. say what it is to be Scientifically, it is also called neoplasia. Cancer is an intractable chronic disease that in many cases cannot be fundamentally cured even if treated with surgery, radiation, and chemotherapy, causing pain to patients and ultimately leading to death. There are many causes of cancer, but internal factors and external factors.
  • the cancer may be solid cancer or hematological cancer, including, but not limited to, squamous cell carcinoma, lung cancer, adenocarcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, cancer near the anus, esophageal cancer, and small intestine cancer.
  • endocrine cancer parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, blood cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver tumor, breast cancer, colon cancer, colorectal cancer, endometrial cancer
  • It may be at least one selected from the group consisting of uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, etc., and more specifically, lung cancer, breast cancer, blood cancer, colon cancer, pancreatic cancer, and these It may be a cancer selected from the group consisting of a combination of.
  • the lung cancer may be non-small cell lung carcinoma or lung papillary adenocarcinoma.
  • the compound according to the present invention may be used for the treatment of lung cancer in T790M mutation-positive patients, EGFR m - patients, and/or patients with resistance to osimertinib, but is not limited thereto.
  • the lung cancer may include EGFR mutation (eg, L858R mutation and/or T790M mutation) and/or MET amplification mutation, but is not limited thereto.
  • the present inventors have confirmed through specific examples that excellent anticancer effects are exerted on cancer cells or animal models containing the mutation when the compound according to the present invention is used in combination with an anticancer agent.
  • breast cancer may be hormone receptor (HR) positive breast cancer, but is not limited thereto.
  • breast cancer may be triple negative breast cancer.
  • breast cancer according to the present invention may include a BRCA1 mutation (eg, 5382C mutation), but is not limited thereto. The present inventors have confirmed through specific examples that excellent anticancer effects are exerted on cancer cells or animal models containing the mutation when the compound according to the present invention is used in combination with an anticancer agent.
  • the blood cancer may be leukemia, lymphoma, multiple myeloma, and the like.
  • the present invention can provide a kit for enhancing the anticancer effect of an anticancer agent, including the compound represented by the above general formula.
  • the present invention provides (i) a compound represented by the general formula or a pharmaceutically acceptable salt thereof; And (ii) it is possible to provide a kit for preventing or treating cancer, including an anticancer agent as an active ingredient.
  • the kit according to the present invention may include, without limitation, other components, compositions, solutions, devices, etc. normally required for the prevention or treatment of cancer in addition to the compounds or anticancer agents, and in particular, suitable use and storage of the compounds according to the present invention It may include instructions for instructing, etc.
  • prevention refers to any action that suppresses or delays the onset of a desired disease
  • treatment means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
  • the effect of preventing and/or treating cancer includes not only an effect of inhibiting the growth of cancer cells, but also an effect of inhibiting deterioration of cancer due to migration, invasion, metastasis, and the like.
  • the term "subject" means a subject in need of prevention or treatment of a disease.
  • the subject may be a human or a mammal including non-human primates, mice, dogs, cats, horses, sheep and cattle.
  • the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and/or diluents commonly used to prepare pharmaceutical compositions in addition to active ingredients.
  • suitable carriers excipients and/or diluents commonly used to prepare pharmaceutical compositions in addition to active ingredients.
  • it can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose , microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • administration means providing a given composition of the present invention to a subject by any suitable method.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is based on the type, severity, and activity of the drug in the patient. , sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.
  • a preferred dosage may be selected according to the condition and body weight of the subject, the severity of the disease, the type of drug, the route and duration of administration.
  • the pharmaceutical composition is administered in an amount of 0.001 to 1000 mg/kg, 0.01 to 100 mg/kg, 0.01 to 10 mg/kg, 0.1 to 10 mg/kg or 0.1 to 1 mg/kg once a day to It can be divided into several doses.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, condition, weight, absorption rate, inactivity rate and excretion rate of the active ingredient in the body, disease type, and concomitant drugs.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
  • the daily dose may be divided and administered once a day to several times.
  • BocThr(OBn)OH (Compound 1; 25.0 g, 80.8 mmol, 1.0 equiv) and NOSu (9.77 g, 84.8 mmol, 1.05 equiv) were dissolved in dichloromethane (150 mL). The mixture was cooled to 0° C. and placed under an inert atmosphere. To the mixture was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.3 g, 84.8 mmol, 1.05 equiv). The mixture was warmed to room temperature and stirred for 20 hours. The mixture was then washed with NH 4 Cl (saturated aqueous) and the phases were separated. The organic layer was dried over MgSO 4 and concentrated under reduced pressure to give compound 2 as a pale yellow oil (35.7 g, >100% yield, assuming quantitative yield) as product.
  • NH 4 Cl saturated aqueous
  • BocThr(OBn)OSu (32.8 g, 80.8 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (200 mL) and a solution of glycine sodium salt hydrate in distilled water (100 mL) was added in one portion. After stirring at room temperature for 6 hours, the mixture was partitioned between ethyl acetate and citric acid (saturated aqueous). The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified on a C18 (400 g) column with 30-70% acetonitrile (0.1% formic acid) in water (0.1% formic acid) as eluent.
  • BocLys(CBz)OH (Compound 4; 27.0 g, 70.9 mmol, 1.0 equiv) and NOSu (9.80 g, 85.1 mmol, 1.2 equiv) were dissolved in dichloromethane (128 mL). The mixture was cooled to 0° C. and placed under an inert atmosphere. To the mixture was then added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (16.3 g, 85.1 mmol, 1.05 equiv). The mixture was warmed to room temperature and stirred for 20 hours. The mixture was then washed with NH 4 Cl (saturated aqueous) and the phases were separated. The organic layer was dried over MgSO 4 and concentrated under reduced pressure to give compound 5 as a pale yellow oil as product (36.7 g, >100% yield, assuming quantitative yield).
  • BocThr(OBn)GlyOH compound 3; 5.61 g, 15.3 mmol, 1.00 equiv
  • compound 8 Lis(Cbz)Thr(OBn)OBn; 10.0 g, 15.3 mmol, 1.0 eq
  • N,N-diisopropylethylamine 5.90 mL, 33.7 mmol, 2.2 eq
  • the mixture was stirred at room temperature under an inert atmosphere and HATU (7.00 g, 18.4 mmol, 1.20 equiv) was added.
  • BocThr(OBn)GlyOH (Compound 3; 5.10 g, 14.0 mmol, 1.05 equiv) and BocThr(OBn)GlyLys(Cbz)Thr(OBn) OBn (Compound 10; 10.8 g, 13.3 mmol, 1.0 equiv) was added N,N -diisopropylethyl amine (5.10 mL, 29.3 mmol, 2.2 equiv). The mixture was stirred at room temperature under an inert atmosphere and HATU (5.60 g, 14.7 mmol, 1.1 equiv) was added.
  • compound 11 (BocThr(OBn)GlyThr(OBn)GlyLys(Cbz)Thr (OBn)OBn; 15.4g, 13.3mmol, 1.00 equivalent taken in the previous step) obtained above was added to 1,4-dioxane at room temperature under nitrogen. (150 mL). To this solution was added 4N HCl in 1,4-dioxane (50 mL) and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and purified on a C18 (120 g) column using 20% acetonitrile (0.1% formic acid) in water (0.1% formic acid) as eluent.
  • Thr(OBn)GlyThr(OBn)GlyLys(Cbz)Thr(OBn)OBn compound 12; 12.7 g, 12.0 mmol in ethyl acetate (150 mL) and N,N -dimethylformamide (25 mL) , 1.0 equiv) and BocGlnOH (3.25 g, 13.2 mmol, 1.1 equiv) was added N,N-diisopropylethylamine (4.60 mL, 26.4 mmol, 2.2 equiv). The mixture was stirred at room temperature under an inert atmosphere and HATU (5.47 g, 14.4 mmol, 1.20 equiv) was added.
  • 3-PhPh-AQTGTGKT (Compound 19-1) was synthesized by reacting Compound 14 with Compound 14 according to Reaction Scheme 9 of Compound 17-1 obtained according to Reaction Scheme 8 below to obtain 3-PhPh-AQTGTGKT as the final target compound.
  • H-Ala-OBzl.HCl (388 mg, 1.80 mmol, 1.2 equiv.) was suspended in ethyl acetate (10 mL) and N,N-diisopropylethylamine (653 ⁇ L, 3.75 mmol, 2.5 equiv.) was added. After stirring at room temperature for 5 minutes, HATU (855 mg, 2.25 mmol, 1.5 equiv) and [1,1'-biphenyl]-3-carboxylic acid (297 mg, 1.50 mmol, 1 equiv) were added and the mixture was brought to room temperature. was stirred for 2 hours.
  • 4-MeOPh-AQTGTGKT (Compound 19-2) was synthesized by reacting Compound 14 and Compound 14 according to Reaction Scheme 11 with Compound 17-2 obtained according to Reaction Scheme 10 to obtain 4-MeOPh-AQTGTGKT as the final target compound.
  • H-Ala-OBzl.HCl (425 mg, 1.97 mmol, 1.2 equiv.) was suspended in ethyl acetate (10 mL) and N,N -diisopropylethylamine (715 ⁇ L, 4.11 mmol, 2.5 equiv.) was added. After stirring at room temperature for 5 minutes, HATU (937 mg, 2.46 mmol, 1.5 equiv) and 4-methoxybenzoic acid (250 mg, 1.64 mmol, 1 equiv) were added and the mixture was stirred at room temperature for 2 hours.
  • reaction mixture was diluted with ethyl acetate then washed with NH 4 Cl (saturated aqueous), NaHCO 3 (saturated aqueous) and brine.
  • the organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the residue was purified on a 25 g column with a 15-50% ethyl acetate in heptane gradient to give compound 16-2 as a colorless solid (360 mg, 70% yield).
  • the dried material was purified on a 30 g C18 column using a 5-30% acetonitrile (0.1% formic acid) gradient in water (0.1% formic acid) and lyophilized to give the compound as a colorless solid (7.0 mg, 10% yield). 19-2 was obtained.
  • 2-PhPh-AQTGTGKT (Compound 19-3) was synthesized by reacting Compound 14 and Compound 14 according to Reaction Scheme 13 with Compound 17-3 obtained according to Reaction Scheme 12 to obtain 2-PhPh-AQTGTGKT as the final target compound.
  • H-Ala-OBzl.HCl (388 mg, 1.80 mmol, 1.2 equiv.) was suspended in ethyl acetate (10 mL) and N,N -diisopropylethylamine (653 ⁇ L, 3.75 mmol, 2.5 equiv.) was added. After stirring at room temperature for 5 minutes, HATU (855 mg, 2.25 mmol, 1.5 equiv) and [1,1'-biphenyl]-2-carboxylic acid (297 mg, 1.50 mmol, 1 equiv) were added and the mixture was brought to room temperature. was stirred for 2 hours.
  • reaction mixture was diluted with ethyl acetate and then washed with NH 4 Cl (saturated aqueous), NaHCO 3 (saturated aqueous) and brine.
  • NH 4 Cl saturated aqueous
  • NaHCO 3 saturated aqueous
  • brine The obtained organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the residue was purified on a 25 g column with a 2-40% ethyl acetate in heptane gradient to give compound 16-3 as a colorless oil (416 mg, 77% yield).
  • the dried material was purified on a 30 g C18 column with a gradient of 5-50% acetonitrile (0.1% formic acid) in water (0.1% formic acid) and lyophilized to give compound 19 as a colorless solid (22.7 mg, 31% yield). -3 was obtained.
  • Ph-AQTGTGKT (Compound 19-4) was synthesized by reacting Compound 14 and Compound 14 according to Reaction Scheme 15 with Compound 17-4 obtained according to Reaction Scheme 14 below to obtain Ph-AQTGTGKT as the final target compound.
  • H-Ala-OBzl.HCl (388 mg, 1.80 mmol, 1.2 equiv.) was suspended in ethyl acetate (10 mL) and N,N -diisopropylethylamine (653 ⁇ L, 3.75 mmol, 2.5 equiv.) was added. After stirring at room temperature for 5 minutes, HATU (855 mg, 2.25 mmol, 1.5 equiv) and benzoic acid (183 mg, 1.50 mmol, 1 equiv) were added and the mixture was stirred at room temperature for 18 hours.
  • reaction mixture was diluted with ethyl acetate then washed with NH 4 Cl (saturated aqueous), NaHCO 3 (saturated aqueous) and brine.
  • NH 4 Cl saturated aqueous
  • NaHCO 3 saturated aqueous
  • brine saturated aqueous
  • the obtained organics were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the residue was purified on a 25 g column with a 2-50% ethyl acetate in heptane gradient to give compound 16-4 as a colorless oil (375 mg, 88% yield).
  • Naphthyl-AQTGTGKT (Compound 19-5) was synthesized by reacting Compound 14 with Compound 14 according to Reaction Scheme 17 with Compound 17-5 obtained according to Reaction Scheme 16 below to synthesize Naphthyl-AQTGTGKT, the final target compound.
  • H-Ala-OBzl.HCl (388 mg, 1.80 mmol, 1.2 equiv.) was suspended in ethyl acetate (10 mL) and N,N -diisopropylethylamine (653 ⁇ L, 3.75 mmol, 2.5 equiv.) was added. After stirring at room temperature for 5 minutes, HATU (855 mg, 2.25 mmol, 1.5 equiv) and 2-naphthoic acid (258 mg, 1.50 mmol, 1 equiv) were added and the mixture was stirred at room temperature for 2 hours.
  • the dried material was purified on a 30 g C18 column with a gradient of 5-40% acetonitrile (0.1% formic acid) in water (0.1% formic acid) and lyophilized to give compound 19 as a colorless solid (23.2 mg, 33% yield). -5 was obtained.
  • Reaction Schemes 19 to 23 are almost similar to Reaction Schemes 1 to 5 except for the presence or absence of a benzyl protecting group, and duplicate descriptions will be omitted.
  • Reaction Scheme 24 and Reaction Scheme 25 were also carried out by a process almost similar to the above-described reaction scheme, so duplicate descriptions will be omitted. Finally, Compound 36 was obtained as a colorless solid (583 mg, 68% yield).
  • a cancer cell line is treated with the compound according to the present invention, and a target anticancer agent (osimertinib or olaparib) or a chemical anticancer agent (allimta or cisplatin) is added simultaneously or 4 hours later, and the combination effect is measured by the degree of cell proliferation through MTT assay did Specifically, 2 ⁇ 10 3 /100 ⁇ l cells were dispensed for each well in a 96-well plate, cultured for 24 hours, the compound according to the present invention was introduced, and after 4 hours, each cancer cell was treated with an anticancer agent. did Treatment concentrations and treatment times of compounds and anticancer agents were specifically described in Examples.
  • CDX Cell line-derived xenograft
  • H820 cells were mixed with Matrigel at a concentration of 5 ⁇ 10 6 cells/mouse at a ratio of 1:1, and each 200 ⁇ l was inoculated once by subcutaneous injection into the flank of a mouse. After completion of the inoculation, it was confirmed that the volume of the formed tumor reached 70 to 130 mm 3 , and then random group separation was performed. The test substance was administered intravenously and orally 7 times at 2-day intervals.
  • H1975 cells were mixed with matrigel at a concentration of 5 ⁇ 10 6 cells/mouse at a ratio of 1:1, and each 200 ⁇ l was inoculated once by subcutaneous injection into the flank of a mouse. After confirming that the volume of tumors formed after inoculation reached 70 to 130 mm 3 , random group separation was performed. After group separation, Osimertinib was orally administered every day, and after tumor growth was suppressed, the time of re-growth was confirmed and co-administration with the test substance was started. The test substance was administered intravenously 7 times at 2-day intervals.
  • a CDX lung cancer animal model using the H1975 cell line was separately prepared.
  • a lung cancer animal model for confirming the combined effect of the compound of the present invention and an anticancer agent before the development of resistance to the anticancer agent was prepared in the following way.
  • H1975 cells were mixed with Matrigel at a concentration of 5 ⁇ 10 6 cells/mouse at a concentration of 5 ⁇ 10 6 cells/mouse in a 4-week-old female BALB/c nude mouse at a ratio of 1:1, and 200 ⁇ l of the cells were inoculated once by subcutaneous injection into the flank of the mouse.
  • osimertinib was orally administered at a dose of 5 mpk daily.
  • the starting day of administration of osimertinib was set to day 1, and the tumor volume was measured twice a week. Beginning on day 50 of osimertinib administration, subjects were subjected to Vehicle; and 3-PhPh-AQTGTGKT 10 mg/kg were separated into two groups and the efficacy of 3-PhPh-AQTGTGKT was evaluated before osimertinib resistance developed.
  • the vehicle group received daily oral administration of osimertinib and intravenous vehicle administration at 2-day intervals, and the combined administration group of osimertinib and 3-PhPh-AQTGTGKT was administered intravenously 7 times every 2 days at a concentration of 10 mg/kg. Tumor size was measured twice a week.
  • a lung cancer animal model for confirming the combined effect of the compound of the present invention and the anticancer agent after the expression of resistance to the anticancer agent was prepared by the following method.
  • H1975 cells were mixed with matrigel at a concentration of 5 ⁇ 10 6 cells/mouse at a ratio of 1:1, and 200 ⁇ l was inoculated once by subcutaneous injection into the flank of a 4-week-old female BALB/c nude mouse.
  • osimertinib was orally administered daily at a dose of 5 mpk when the volume of the formed tumor reached a size of 70 to 300 mm 3 .
  • the starting date of osimertinib administration was set to day 1, and the tumor volume was measured twice a week.
  • the vehicle group received daily oral administration of osimertinib and intravenous administration of vehicle every 2 days, and the group administered with osimertinib and 3-PhPh-AQTGTGKT at 5mg/kg or 10mg/kg concentration every 2 days for 7 days.
  • the size of the tumor was measured twice a week while administering a single tail vein.
  • HCC1806 cells were mixed with matrigel at a concentration of 5 ⁇ 10 6 cells/mouse at a concentration of 5 ⁇ 10 6 cells/mouse in a 4-week-old female BALB/c nude mouse at a ratio of 1:1, and 200 ⁇ l of the cells were inoculated once subcutaneously into the flank of the mouse. Random group separation was performed when the volume of tumors formed after completion of inoculation reached a size of 150 to 250 mm 3 .
  • AQTGTGKT 3-PhPh-AQTGTGKT, or Ph-AQTGTGKT was administered intravenously 9 times every 2 days, and cisplatin was intraperitoneally administered 3 times every 7 days, and the volume was calculated by measuring the short and long axes of the tumor. and showed the tumor growth curve.
  • tumor tissues were provided in HBSS media in a 50 ml tube and transplanted into NOD/SCID mice within 24 hours.
  • SC subcutaneously
  • FBS:DMSO ratio 9:1
  • Tissues embedded in paraffin were cut and attached to slides to a thickness of 4 ⁇ m, dried well, and then IHC experiments were performed. After deparaffinization of each slide, endogenous enzymes were removed using citrate buffer (pH 6.0). Subsequently, the P-Beclin1 antibody was diluted 1:100 and treated at 4°C for 15 hours. After washing repeatedly with TBST washing buffer solution 4 times, rabbit HRP was treated for secondary antibody reaction and reacted at room temperature for 30 minutes. When a substrate for antibody reaction was added and color development appeared, the slide was washed and sealed, and the result was read after scanning the slide.
  • Example 1 Anti-cancer effects of AQTGTGKT or its analogues in combination with targeted/chemo-anticancer agents in lung cancer cells
  • H1975 was treated with 4-PhPh-AQTGTGKT at a concentration of 2 ⁇ M, and simultaneously treated with osimertinib at a concentration of 1 ⁇ M alone or in combination, and then 48 hours later, cell proliferation inhibitory effects were compared.
  • 4-PhPh-AQTGTGKT was treated alone, cell proliferation was reduced by about 12% compared to the control group, and when osimertinib was treated alone, cell proliferation was reduced by about 5% compared to the control group. decreased.
  • the combined treatment of 4-PhPh-AQTGTGKT and osimertinib showed an inhibitory effect on cell proliferation by about 24% (FIG. 1b).
  • H1975 was treated with Ac-AQTGTGKT at a concentration of 10 ⁇ M, and at the same time osimertinib was treated alone or in combination at a concentration of 0.5 ⁇ M, and the cell proliferation inhibitory effect was compared 48 hours later.
  • Ac-AQTGTGKT was treated alone, cell proliferation was reduced by about 14% compared to the control group, and when osimertinib was treated alone, cell proliferation was reduced by about 12% compared to the control group.
  • the combined treatment of Ac-AQTGTGKT and osimertinib showed an inhibitory effect on cell proliferation by about 26% (FIG. 1c).
  • H1975 was treated with 4-MeOPh-AQTGTGKT at a concentration of 10 ⁇ M, and at the same time, the target anticancer drug osimertinib was treated alone or in combination at a concentration of 0.5 ⁇ M, and the cell proliferation inhibitory effect was compared 48 hours later.
  • 4-MeOPh-AQTGTGKT was treated alone, cell proliferation was reduced by about 6% compared to the control group, and when osimertinib was treated alone, cell proliferation was reduced by about 21% compared to the control group. decreased.
  • the combined treatment of 4-MeOPh-AQTGTGKT and osimertinib showed an inhibitory effect on cell proliferation by about 27% (FIG. 1d).
  • H1975 was treated with 2-PhPh-AQTGTGKT, Ph-AQTGTGKT, or Naphtyl-AQTGTGKT at a concentration of 10 ⁇ M, and at the same time, the target anticancer drug osimertinib was treated alone or in combination at a concentration of 0.5 ⁇ M, and 24 hours later the cells were treated. The proliferation inhibitory effect was compared.
  • H1975/OR was treated with 3-PhPh-AQTGTGKT at a concentration of 5 ⁇ M, and 4 hours later, the target anticancer drug osimertinib was treated alone or in combination at a concentration of 2.5 ⁇ M, and then the cell proliferation inhibitory effect was compared 68 hours later.
  • the target anticancer drug osimertinib was treated alone or in combination at a concentration of 2.5 ⁇ M, and then the cell proliferation inhibitory effect was compared 68 hours later.
  • FIG. 1h when 3-PhPh-AQTGTGKT was treated alone, cell proliferation was reduced by about 17% compared to the control group, and when osimertinib was treated alone, cell proliferation was reduced compared to the control group. proliferation was reduced by about 7%.
  • the combination treatment of 3-PhPh-AQTGTGKT and osimertinib showed an inhibitory effect on cell proliferation by about 30%.
  • H1975/OR was treated with 3-PhPh-AQTGTGKT at a concentration of 5 ⁇ M, and 4 hours later, the anticancer drug Alimta was treated alone or in combination at a concentration of 0.1 ⁇ M, and then the cell proliferation inhibitory effect was compared 72 hours later.
  • the cell proliferation inhibitory effect was compared 72 hours later.
  • FIG. 2b when 3-PhPh-AQTGTGKT was treated alone, cell proliferation was reduced by about 6.5% compared to the control group, and when Alimta was treated alone, cell proliferation compared to the control group. This decreased by about 8.3%.
  • the combined treatment of 3-PhPh-AQTGTGKT and Alimta showed an inhibitory effect on cell proliferation by about 20%.
  • H1975 was treated with 2-PhPh-AQTGTGKT, Ph-AQTGTGKT, or Naphtyl-AQTGTGKT at a concentration of 10 ⁇ M, and simultaneously treated with Alimta at a concentration of 0.1 ⁇ M alone or in combination, and then the cell proliferation inhibitory effect was compared 72 hours later. did
  • the anticancer effect by the triple therapy of the compound of the present invention, a target anticancer agent, and a chemotherapy agent was confirmed.
  • the lung cancer cell killing effect was confirmed by the triple combination of 3-PhPh-AQTGTGKT, osimertinib, and allimta, wherein 3-PhPh-AQTGTGKT was used at a concentration of 5 ⁇ M, and osimertinib and allimta at a concentration of 2.5 ⁇ M, respectively.
  • the H1975 cells were treated at concentrations of ⁇ M and 100 nM for 72 hours (concentrations treated in an experiment to confirm the anticancer effect of combination with 3-PhPh-AQTGTGKT, respectively).
  • the anticancer effect of the triple combination was compared with the 3-PhPh-AQTGTGKT alone treatment group and the combination treatment group of osimertinib and Alimta.
  • the group treated with the triple combination of 3-PhPh-AQTGTGKT, osimertinib, and allimta inhibited cell growth by about 35% compared to the control group, and thus the group treated with 3-PhPh-AQTGTGKT alone or the group treated with osimertinib and allimta inhibited cell growth by about 35%.
  • the combination treatment group it was found to have a much better cell proliferation inhibitory effect (FIG. 3).
  • H820 was treated with AQTGTGKT at a concentration of 10 ⁇ M, and at the same time, the target anticancer drug osimertinib was treated alone or in combination at a concentration of 5 ⁇ M, and then the cell proliferation inhibitory effect was compared 48 hours later.
  • the cell proliferation inhibitory effect was compared 48 hours later.
  • AQTGTGKT was treated alone
  • cell proliferation was reduced by about 15% compared to the control group
  • osimertinib was treated alone
  • cell proliferation was decreased compared to the control group. decreased by about 28%.
  • the combination treatment of AQTGTGKT and osimertinib showed about 40% of cell proliferation inhibitory effect.
  • H820 was treated with 3-PhPh-AQTGTGKT at a concentration of 40 ⁇ M, and 4 hours later, the target anticancer drug osimertinib was treated alone or in combination at a concentration of 6 ⁇ M, and then the cell proliferation inhibitory effect was compared 72 hours later.
  • the target anticancer drug osimertinib was treated alone or in combination at a concentration of 6 ⁇ M, and then the cell proliferation inhibitory effect was compared 72 hours later.
  • the target anticancer drug osimertinib was treated alone or in combination at a concentration of 6 ⁇ M, and then the cell proliferation inhibitory effect was compared 72 hours later.
  • the target anticancer drug osimertinib was treated alone or in combination at a concentration of 6 ⁇ M, and then the cell proliferation inhibitory effect was compared 72 hours later.
  • the combined treatment of 3-PhPh-AQTGTGKT and osimertinib showed an inhibitory effect on cell
  • non-small cell lung cancer cell line PC9/OR was treated with 3-PhPh-AQTGTGKT at a concentration of 25 ⁇ M, and 4 hours later, osimertinib, a target anticancer drug, was added at a concentration of 4 ⁇ M.
  • Cell toxicity was compared 68 hours after treatment alone or in combination.
  • Examples 1.1 to 1.3 show that AQTGTGKT or an analog thereof according to the present invention in lung cancer cells; And it shows that combination therapy of targeted anticancer agents is much more effective than monotherapy.
  • Example 2 Anticancer effect of AQTGTGKT or its analogue in breast cancer cells by target/chemotherapy combination
  • breast cancer cell line HCC1937 cells were treated with AQTGTGKT at a concentration of 5 ⁇ M, and at the same time, the target anticancer drug, Olaparib, was treated alone or in combination at a concentration of 2.5 ⁇ M, and then the cell proliferation inhibitory effect was compared 24 hours later.
  • the target anticancer drug Olaparib
  • HCC1937 was treated with 3-PhPh-AQTGTGKT at a concentration of 10 ⁇ M, and at the same time, the target anticancer drug olaparib was treated alone or in combination at a concentration of 2.5 ⁇ M, and then the cell proliferation inhibitory effect was compared 24 hours later.
  • the combination treatment of 3-PhPh-AQTGTGKT and olaparib showed an inhibitory effect on cell proliferation by about 8.2%.
  • HCC1937 was treated with 4-phph-AQTGTGKT, Ac-AQTGTGKT, 2-phph-AQTGTGKT, ph-AQTGTGKT, or Naphtyl-AQTGTGKT at a concentration of 10 ⁇ M, and simultaneously treated with olaparib at a concentration of 2.5 ⁇ M alone or in combination After 48 or 72 hours, the cell proliferation inhibitory effect was compared.
  • HCC1937 cells were treated with 4-MeOph-AQTGTGKT at a concentration of 5 ⁇ M, and at the same time, cisplatin, a chemotherapeutic agent, was treated alone or in combination at a concentration of 4 ⁇ M, and the cell proliferation inhibitory effect was compared 48 hours later.
  • cisplatin a chemotherapeutic agent
  • HCC1937 was treated with 3-PhPh-AQTGTGKT at a concentration of 10 ⁇ M and simultaneously treated with cisplatin at a concentration of 2 ⁇ M alone or in combination, and the cell proliferation inhibitory effect was compared 72 hours later.
  • FIG. 7b when 3-PhPh-AQTGTGKT was treated alone, cell proliferation was reduced by about 3% compared to the control group, and when cisplatin was treated alone, cell proliferation decreased compared to the control group. Growth was reduced by about 10%.
  • the combined treatment of 3-PhPh-AQTGTGKT and cisplatin showed an inhibitory effect on cell proliferation by about 20%.
  • HCC1937 was treated with 4-phph-AQTGTGKT, Ac-AQTGTGKT, 2-phph-AQTGTGKT, ph-AQTGTGKT, or Naphtyl-AQTGTGKT at a concentration of 10 ⁇ M, and simultaneously treated with cisplatin at a concentration of 2 or 4 ⁇ M alone or in combination After 72 hours, the cell proliferation inhibitory effect was compared.
  • Example 3 Evaluation of anticancer effects according to combination therapy of 3-PhPh-AQTGTGKT and osimertinib
  • PC9/OR lung cancer cell lines were treated with osimertinib and 3-PhPh-AQTGTGKT in combination and then treated with osimertinib alone.
  • the experiment was conducted by dividing the group into two groups, first treated with osimertinib alone and then treated with osimertinib and 3-PhPh-AQTGTGKT in combination.
  • combination 1 (Combo 1) was treated with osimertinib 4 ⁇ M and 3-PhPh-AQTGTGKT 25 ⁇ M for 3 days, and after replacing the medium, osimertinib was treated alone for 3 days
  • combination 2 ( Combo 2) was treated with 4 ⁇ M of osimertinib alone for 3 days, and after replacing the medium, 4 ⁇ M of osimertinib and 25 ⁇ M of 3-PhPh-AQTGTGKT were treated for 3 days. Then, the cells were stained with crystal violet, and cell growth was measured at 570 nm using an absorber.
  • the PC9/OR lung cancer cell line was treated with osimertinib and 3-PhPh-AQTGTGKT in combination and then osimertinib was treated alone, osimertinib. and 3-PhPh-AQTGTGKT were divided into groups continuing the combined treatment, and the experiment was conducted.
  • combination 1 (Combo 1) was treated with osimertinib 1 ⁇ M and 3-PhPh-AQTGTGKT 25 ⁇ M for 3 days, and after replacing the medium, osimertinib was treated alone for 3 days, and combination 2 (combo 2) was treated with 1 ⁇ M of osimertinib and 25 ⁇ M of 3-PhPh-AQTGTGKT for 3 days, and after replacing the medium, the treatment was repeated with 1 ⁇ M of osimertinib and 25 ⁇ M of 3-PhPh-AQTGTGKT for 3 days. Then, the cells were stained with crystal violet, and cell growth was measured at 570 nm using an absorber.
  • Example 4 Anticancer effect of AQTGTGKT analog and osimertinib combined use in lung cancer animal model prepared using lung cancer cell line
  • the combined efficacy of the compound of the present invention and osimertinib was evaluated after expression of osimertinib resistance in a lung cancer animal model using the H1975 cell line.
  • H1975 cell line After inoculation of the H1975 cell line into 4-week-old female Balb/C nude mice, tumor formation and growth were observed, and the volume was calculated by measuring the short and long axes of the tumor. When the volume of the tumor reached 70-120 mm 3 , random groups were separated and negative control groups, PBS and osimertinib 5 mpk were orally administered daily.
  • osimertinib 5 mpk was orally administered daily and PBS was administered intravenously every 2 days (Osimertinib + PBS group); and 5 mpk of osimertinib was orally administered daily and 10 mpk of 3-PhPh-AQTGTGKT (osimertinib + 3-PhPh-AQTGTGKT group) was divided into groups administered intravenously every 2 days, and efficacy was evaluated.
  • the osimertinib + PBS group measured an average of 692.6 mm 3 and the tumor size of the osimertinib + 3-PhPh-AQTGTGKT group was measured as 364.7 mm 3 , osimertinib It was confirmed that the tumor size was suppressed by about 52% in the osimertinib + 3-PhPh-AQTGTGKT administration group compared to the +PBS group. During the experiment, no weight loss or death was observed in all subjects.
  • the lung cancer PDX model was prepared by transplanting PDX tissue containing the EGFR L858R mutation, and the volume of the tumor formed after the transplantation of tumor tissue was completed was 300 to 350 mm 3 size.
  • the groups were randomly separated as follows: Lazertinib 10mpk alone administration group; 3-PhPh-AQTGTGKT 10mg/kg alone administration group; and Lazertinib and 3-PhPh-AQTGTGKT combined administration group.
  • Lazertinib was orally administered daily at a concentration of 10 mpk and 3-PhPh-AQTGTGKT was administered intravenously at a concentration of 10 mpk, and the tumor growth curve over time was observed.
  • the Lazertinib alone administration group and the 3-PhPh-AQTGTGKT alone administration group showed suppression of tumor growth compared to the control group after 10 days, and in the case of the Lazertinib and 3-PhPh-AQTGTGKT combination administration group After 7 days, the inhibitory effect compared to the control group was shown. After 13 days, compared to Lazertinib or 3-PhPh-AQTGTGKT alone, the tumor suppression effect began to appear predominantly in the Lazertinib and 3-PhPh-AQTGTGKT combined administration group.
  • the tumor growth was suppressed statistically significantly in the group administered with Lazertinib or 3-PhPh-AQTGTGKT alone compared to the control group (P ⁇ 0.001), and Lazertinib and 3-PhPh-AQTGTGKT combined administration group showed more significant suppression of tumor growth compared to the control group (P ⁇ 0.001).
  • the 3-PhPh-AQTGTGKT monotherapy P ⁇ 0.001
  • Lazertinib P ⁇ 0.05
  • the lung cancer PDX model was prepared by transplanting PDX tissue containing the EGFR L858R mutation, and the volume of the tumor formed after completion of transplantation of tumor tissue was 300 to 350 mm 3 to 3 in size. 5mpk alone administration group by separating random groups when 3-PhPh-AQTGTGKT 10 mg/kg alone administration group; The tumor growth curve was observed by dividing into osimertinib and 3-PhPh-AQTGTGKT co-administration groups.
  • the tumor growth of the osimertinib monotherapy group and the 3-PhPh-AQTGTGKT monotherapy group was suppressed compared to the control group after 10 days. It was confirmed that tumor growth was suppressed compared to the control group from day one. In particular, after the 13th day, the tumor suppression effect began to appear predominantly in the combined administration group of osimertinib and 3-PhPh-AQTGTGKT compared to the group administered with osimertinib or 3-PhPh-AQTGTGKT alone.
  • osimertinib or 3-PhPh-AQTGTGKT monotherapy group inhibited tumor growth statistically significantly compared to the control group (P ⁇ 0.001 ), and it was confirmed that the combination administration group of osimertinib and 3-PhPh-AQTGTGKT inhibited tumor growth more significantly than the control group (P ⁇ 0.001).
  • tumor growth was suppressed statistically significantly in the combined administration group compared to the single administration group of osimertinib or 3-PhPh-AQTGTGKT (P ⁇ 0.001).
  • a lung cancer animal model in which resistance to the anticancer agent was expressed was prepared by long-term administration of an anticancer agent (osimertinib) after transplantation of a lung cancer cell line, and after the expression of resistance to the anticancer agent, the compound of the present invention and the anticancer agent The combination effect was confirmed.
  • an anticancer agent osimertinib
  • osimertinib was orally administered daily for 54 days to a lung cancer animal model prepared by injecting the H1975 cell line, and tumor growth was initially reduced by osimertinib, then Thereafter, the animal model in which the tumor showed growth again was judged as an individual that had acquired drug resistance.
  • Models receiving oral administration of osimertinib for 54 days were Vehicle; 3-PhPh-AQTGTGKT 5 mg/kg administration group; and 10 mg/kg administration group, and the efficacy of 3-PhPh-AQTGTGKT was evaluated.
  • the vehicle group received daily oral administration of osimertinib and intravenous administration of vehicle every 2 days, and the group administered with osimertinib and 3-PhPh-AQTGTGKT at 5mg/kg or 10mg/kg concentration every 2 days for 7 days.
  • the size of the tumor was measured twice a week while administering a single tail vein.
  • the tumor volume began to decrease according to the number of osimertinib administrations, and the growth of the tumor was suppressed. It was confirmed that tumor growth was inhibited compared to the group. After 7 administrations (14 days after administration), a statistically significant difference began to appear in the tumor growth curve in the combination administration group compared to the PBS group (P ⁇ 0.01). In the case of the 3-PhPh-AQTGTGKT 5mpk administration group, tumor growth showed a lower growth rate than the PBS group after 3 administrations, and showed a statistically significant difference compared to the PBS group by suppressing up to 7 administrations (P ⁇ 0.01) . Results are shown in FIG. 12 . During the experiment, no weight loss or death was observed.
  • the tumor volume began to decrease according to the number of administrations of osimertinib, and the tumor growth was inhibited, and 50 days after administration before the development of resistance to osimertinib, it was divided into osimertinib alone administration group and 3-PhPh-AQTGTGKT 10mg/kg combined administration group, and anticancer treatment according to 3-PhPh-AQTGTGKT administration effect was observed.
  • the tumor showed a tendency to grow again from the 54th day of administration, and the resistance was expressed after the 58th day of administration, resulting in the promotion of tumor growth.
  • the co-administered group of osimertinib and 3-PhPh-AQTGTGKT 10mg/kg tumors did not re-grow until the lapse of 64 days and the tumors were maintained at a low size. Although tumor regrowth was observed after 64 days, the size of the tumor was very small compared to the single administration group.
  • tumors of the 3-PhPh-AQTGTGKT 10mpk-administered group showed a lower growth rate compared to the PBS group until day 82 of administration. During the experiment, no weight loss or death was observed.
  • Example 7 Anticancer effect of AQTGTGKT analog and osimertinib combined use in breast cancer animal model prepared using HCC1806 cell line
  • a breast cancer animal model was prepared by transplanting a breast cancer cell line into a mouse, and the combined effect of the compound of the present invention and an anticancer agent was confirmed.
  • AQTGTGKT, 3-PhPh-AQTGTGKT, or Ph-AQTGTGKT was administered intravenously 9 times every 2 days for 18 days at a dose of 10 mg/kg to nude mice transplanted with HCC1806 cell line, which is an animal model for breast cancer, and cisplatin was administered at 5 mg/kg. Tumor growth was compared after intraperitoneal administration three times at 7-day intervals.
  • the AQTGTGKT alone group, the cisplatin alone group, and the combination administration group all showed a pattern of suppression of tumor growth compared to the control group from the 12th day.
  • the cisplatin and AQTGTGKT combination group showed a statistically It was confirmed that it decreased significantly (p ⁇ 0.001).
  • the tumor size and growth curve of the combined administration group decreased (FIG. 14a).
  • the 3-PhPh-AQTGTGKT alone group, the cisplatin alone group, and the cisplatin and 3-PhPh-AQTGTGKT combined group showed a tendency to suppress tumor growth compared to the control group from day 9, and tumor growth was observed 18 days after administration. A statistically significant decrease compared to the control group was confirmed (p ⁇ 0.001). In addition, it was observed that the tumor size and growth curve decreased in the combined administration group compared to the single administration group (FIG. 14b).
  • the expression of p-Beclin1 was decreased in the group treated with 3-PhPh-AQTGTGKT alone when compared to the group administered with osimertinib alone in the xenograft lung cancer animal model, and the expression of 3-PhPh -AQTGTGKT and osimertinib showed an even greater decrease in the group.
  • the present invention relates to a compound for enhancing the anticancer effect of currently used target anticancer agents and chemotherapy agents, and more particularly, to a composition containing an oligopeptide AQTGTGKT or an analog thereof that exhibits excellent anticancer effects without side effects.
  • a significant synergistic effect can be provided in terms of cancer growth inhibitory effect compared to the control group and each single treatment group.
  • the oligopeptides and analogs thereof are expected to be used in combination with anticancer agents for various carcinomas because they have a small molecular weight compared to antibodies, so there is less concern about immune reactions and they are easily penetrated into tissues.

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  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un composé pour améliorer les effets anticancéreux d'agents anticancéreux ciblés et d'agents chimiothérapeutiques actuellement utilisés, et, plus particulièrement, une composition comprenant l'oligopeptide AQTGTGKT, qui présente un excellent effet anticancéreux sans aucun effet secondaire, ou un analogue de celui-ci ; et similaire. Lorsque l'oligopeptide ou l'analogue de celui-ci, selon la présente invention, est mélangé avec un agent anticancéreux pour un traitement combiné, un effet synergique significatif en ce qui concerne les effets inhibiteurs sur la croissance du cancer, par rapport à un groupe témoin et aux groupes de traitement individuels respectifs, peut être fourni. En outre, étant donné qu'un médicament anticancéreux à faible dose peut présenter un excellent effet anticancéreux combiné, les effets secondaires, tels qu'une altération des fonctions et des activités, qui apparaissent dans les tissus normaux, un dysfonctionnement de la moelle osseuse, des troubles gastro-intestinaux, une alopécie et une résistance aux médicaments anticancéreux peuvent être réduits au minimum. De plus, l'oligopeptide et son analogue ont les avantages d'avoir un poids moléculaire inférieur à celui d'un anticorps de telle sorte que les réponses immunitaires sont moins préoccupantes, et de pénétrer facilement dans les tissus, et il est donc prévu de les utiliser en combinaison avec des agents anticancéreux pour divers types de cancer.
PCT/KR2022/013879 2021-09-17 2022-09-16 Composition pharmaceutique pour améliorer l'effet anticancéreux d'un médicament anticancéreux Ceased WO2023043261A1 (fr)

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KR20210125230 2021-09-17
KR10-2021-0125230 2021-09-17
KR1020220116621A KR102786112B1 (ko) 2021-09-17 2022-09-15 항암제의 항암 효과 증진용 약학적 조성물
KR10-2022-0116621 2022-09-15

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KR20120099440A (ko) * 2009-10-22 2012-09-10 임페리얼 이노베이션스 리미티드 Ｇａｄｄ45β를 표적으로 하는 물질
WO2016099188A1 (fr) * 2014-12-18 2016-06-23 주식회사 엘베이스 Peptide ayant huit séquences d'acides aminés dérivées de cage et conservant une activité anticancéreuse et une activité visant à promouvoir la sensibilité à un médicament anticancéreux de cellules cancéreuses résistant à des médicaments anti-cancéreux
KR20210118764A (ko) * 2020-03-23 2021-10-01 주식회사 엘베이스 암의 예방 또는 치료용 약학적 조성물

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WO2016099188A1 (fr) * 2014-12-18 2016-06-23 주식회사 엘베이스 Peptide ayant huit séquences d'acides aminés dérivées de cage et conservant une activité anticancéreuse et une activité visant à promouvoir la sensibilité à un médicament anticancéreux de cellules cancéreuses résistant à des médicaments anti-cancéreux
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