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WO2021241913A1 - Composé de dibenzamide phénylène et composition pharmaceutique pour prévenir ou traiter des maladies cancéreuses le comprenant en tant que principe actif - Google Patents

Composé de dibenzamide phénylène et composition pharmaceutique pour prévenir ou traiter des maladies cancéreuses le comprenant en tant que principe actif Download PDF

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WO2021241913A1
WO2021241913A1 PCT/KR2021/005808 KR2021005808W WO2021241913A1 WO 2021241913 A1 WO2021241913 A1 WO 2021241913A1 KR 2021005808 W KR2021005808 W KR 2021005808W WO 2021241913 A1 WO2021241913 A1 WO 2021241913A1
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Prior art keywords
group
compound
cancer
substituted
unsubstituted
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English (en)
Korean (ko)
Inventor
오상철
김정림
오선희
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HEDGEHOG Inc
Korea University Research and Business Foundation
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HEDGEHOG Inc
Korea University Research and Business Foundation
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Priority claimed from KR1020210048315A external-priority patent/KR102709756B1/ko
Application filed by HEDGEHOG Inc, Korea University Research and Business Foundation filed Critical HEDGEHOG Inc
Publication of WO2021241913A1 publication Critical patent/WO2021241913A1/fr
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues

Definitions

  • the present invention relates to a novel phenylene dibenzamide compound and a pharmaceutical composition for preventing or treating cancer diseases comprising the same as an active ingredient.
  • Colorectal cancer currently has the third highest incidence in Korea, the second highest in men and the third highest in women, and the incidence and mortality rates are continuously increasing. In addition, considering that lifestyles are gradually becoming westernized, the increase in colorectal cancer is expected to accelerate further, so active interest and research on colorectal cancer in our society is absolutely necessary. In addition, colorectal cancer has a high recurrence rate of up to 50% after being cured, making the risk more serious. Surgical radical resection is the main treatment for colorectal cancer, and in the case of early colorectal cancer, a good survival rate is expected with only surgery.
  • cytotoxic drugs such as irinotecan (IRI) and oxaliplatin have been used as adjuvant therapy for the treatment of colorectal cancer so far.
  • drugs such as Cetuximab and Bevacizumab, known as selective therapeutic agents, are being used as a treatment for colorectal cancer.
  • drugs widely used for chemotherapy of colorectal cancer have serious side effects by killing not only colorectal cancer cells but also normal cells, and have practical limitations in treatment because they are focused on suppressing the cancerous process.
  • the hedgehog signaling pathway can induce cell fate determination, differentiation, and proliferation during development by acting on peripheral cells.
  • the hedgehog signaling pathway is involved in the maintenance of stem cells in adults, and it is also used in various congenital diseases such as Pallister Hall syndrome and VATER syndrome, and cancers such as medullary blast carcinoma, lung cancer, gastric cancer, esophageal cancer, and pancreatic cancer. As its involvement is known, its clinical importance is being highlighted. It is known by several reports that the hedgehog/GLI signaling pathway induces various types of cancer when overexpressed by mutations or environmental factors.
  • Hedgehog signaling is known as a signal transduction system that controls the self-replication and proliferation of cancer stem cells, and these results suggest the possibility as a new target therapy for the hedgehog signaling pathway to block cancer. It is known that the growth of cancer cells is inhibited when treated with GANT61 (GLI inhibitor), an inhibitor that blocks the SHH/GLI signaling pathway.
  • GANT61 GANT61
  • Cancer is currently one of the most deadly diseases worldwide, and the age of cancer onset is gradually decreasing while the average lifespan is gradually increasing, so the incidence of cancer is expected to increase further. necessary.
  • the search for combination anticancer drugs that can maximize the effect of existing anticancer drugs in cancer cells is becoming very important. Accordingly, we intend to develop a new small molecule compound that effectively inhibits hedgehog/GLI signaling, and propose a method for preventing and treating cancer using this compound.
  • An object of the present invention is to control the expression and activity of GLI by targeting GLI in the hedgehog signaling pathway, thereby suppressing the hedgehog signaling pathway, and by combining it with a topoisomerase inhibitor, GLI expression and activity
  • An object of the present invention is to provide a novel compound capable of further improving the inhibitory ability.
  • Another object of the present invention is to control the expression and activity by targeting GLI in the hedgehog signaling pathway, thereby suppressing the hedgehog signaling pathway, and by combining it with a topoisomerase inhibitor, GLI expression and
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer diseases comprising a novel compound capable of further improving the activity inhibition ability as an active ingredient.
  • Another object of the present invention is to control the expression and activity by targeting GLI in the hedgehog signaling pathway, thereby suppressing the hedgehog signaling pathway, and by using in combination with a topoisomerase inhibitor
  • An object of the present invention is to provide a screening method for a novel compound capable of further improving the ability to inhibit GLI expression and activity.
  • a compound represented by the following Structural Formula 1 is provided.
  • R 1 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
  • R 2 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, Or a substituted or unsubstituted C1 to C30 heteroaryl group,
  • R 3 is a hydrogen atom, a nitro group, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 hetero a cycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group.
  • R 1 is a C1 to C10 alkoxy group, or a C1 to C10 alkyl group,
  • R 2 is a hydrogen atom, or a C1 to C10 alkyl group
  • R 3 may be a nitro group or a C1 to C10 alkoxy group.
  • the compound represented by Structural Formula 1 may be represented by Structural Formula 2 or 3 below.
  • R 1 is a C1 to C10 alkoxy group, or a C1 to C10 alkyl group,
  • R 2 is a hydrogen atom, or a C1 to C10 alkyl group
  • R 3 is a nitro group or a C1 to C10 alkoxy group.
  • the compound represented by Structural Formula 1 may be the following compound 1 or compound 2.
  • compositions for preventing or treating cancer comprising the following Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the pharmaceutical composition for preventing or treating cancer diseases may further include a topoisomerase inhibitor.
  • the topoisomerase inhibitor may be at least one selected from irinotecan, topotecan, and belotecan.
  • the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, lung cancer, pancreatic cancer, basal cell cancer, brain cancer, liver cancer, and breast cancer.
  • the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer and lung cancer.
  • the pharmaceutical composition for preventing or treating cancer may be for inhibiting hedgehog signaling.
  • the pharmaceutical composition for preventing or treating cancer diseases may be for inhibiting GLI transcriptional activity.
  • GLI reporter NIH3t3 cell line of N,N'-1,3-phenylene dibenzamide (N,N'-1,3-phenylene dibenzamide)-based compound library for cancer disease prevention or treatment comprising the step of A screening method is provided.
  • the GLI reporter NIH3t3 cell line may include a luciferase gene that is controlled according to the expression level of GLI.
  • the novel compound of N,N'-1,3-phenylene dibenzamide represented by Structural Formula 1 of the present invention targets GLI in the Hedgehog signaling pathway.
  • GLI in the Hedgehog signaling pathway.
  • compound 1 or compound 2 with high GLI transcriptional activity inhibition ability screened from the N,N'-1,3-phenylene dibenzamide-based compound library of the present invention is It is useful for preventing or treating cancer diseases, and in particular, it can exhibit a synergistic effect in preventing or treating cancer diseases by using it in combination with a topoisomerase inhibitor.
  • 1 is a schematic diagram of the hedgehog signaling pathway.
  • Example 2 is a result of confirming the ability to inhibit GLI transcriptional activity according to Example 1.
  • FIG. 3 is a result of confirming Hedgehog/GLI expression in normal colon cells and colorectal cancer cell lines according to Experimental Example 1.
  • FIG. 5 is a cell growth measurement result according to the hedgehog / GLI inhibitor of Experimental Example 2 and irinotecan (IRI) combined treatment.
  • substituted means that at least one hydrogen atom is deuterium, C1 to C30 alkyl group, C3 to C30 cycloalkyl group, C2 to C30 heterocycloalkyl group, C1 to C30 halogenated alkyl group, C6 to C30 aryl group, C1 to C30 heteroaryl group, C1 to C30 alkoxy group, C3 to C30 cycloalkoxy group, C1 to C30 heterocycloalkoxy group, C2 to C30 alkenyl group, C2 to C30 alkynyl group, C6 to C30 aryloxy group, C1 to C30 heteroaryloxy group, Silyloxy group (-OSiH 3 ), -OSiR 1 H 2 (R 1 is a C1 to C30 alkyl group or C6 to C30 aryl group), -OSiR 1 R 2 H (R 1 and R 2 are each independently a C1 to C30 alkyl group or C6
  • two adjacent substituents among the above substituents may be fused to form a saturated or unsaturated ring.
  • the carbon number range of the alkyl group or aryl group in the "substituted or unsubstituted C1 to C30 alkyl group” or “substituted or unsubstituted C6 to C30 aryl group” is unsubstituted without considering the portion in which the substituent is substituted. It refers to the total number of carbon atoms constituting the alkyl part or the aryl part when viewed as formed. For example, a phenyl group substituted with a butyl group at the para position corresponds to an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.
  • hetero means that one functional group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S and P, and the remainder is carbon.
  • hydrogen means singlet, deuterium, or tritium, unless otherwise defined.
  • alkyl group refers to an aliphatic hydrocarbon group unless otherwise defined.
  • the alkyl group may be a “saturated alkyl group” that does not contain any double or triple bonds.
  • the alkyl group may be an "unsaturated alkyl group" containing at least one double bond or triple bond.
  • Alkyl groups whether saturated or unsaturated, may be branched, straight-chain or cyclic.
  • the alkyl group may be a C1 to C30 alkyl group. More specifically, it may be a C1 to C20 alkyl group, a C1 to C10 alkyl group, or a C1 to C6 alkyl group.
  • a C1 to C4 alkyl group has 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. It indicates that it is selected from the group consisting of.
  • alkyl group examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group, an ethenyl group, a propenyl group, a butenyl group, a cyclopropyl group, a cyclo It means a butyl group, a cyclopentyl group, a cyclohexyl group, and the like.
  • Cycloalkyl group includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) functional groups.
  • Heterocycloalkyl group means that the cycloalkyl group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S and P, and the remainder is carbon.
  • the heterocycloalkyl group is a fused ring, at least one ring of the fused ring may include 1 to 4 hetero atoms.
  • Aryl group includes monocyclic or fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) functional groups.
  • Heteroaryl group means that the aryl group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S and P, and the remainder is carbon.
  • the heteroaryl group is a fused ring, at least one ring among the fused rings may include 1 to 4 hetero atoms.
  • the number of atoms in the ring is the sum of the number of carbon atoms and the number of non-carbon atoms.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., tartaric acid , organic carboxylic acids such as formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid acid addition salts formed with sulfonic
  • pharmaceutically acceptable salts of carboxylic acids include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine, and the like.
  • the compounds of formulas 1, 2 or 3 according to the present invention can also be converted into their salts by conventional methods.
  • novel phenylene dibenzamide-based compound of the present invention may be represented by the following structural formula (1).
  • R 1 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
  • R 2 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, Or a substituted or unsubstituted C1 to C30 heteroaryl group,
  • R 3 is a hydrogen atom, a nitro group, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 hetero a cycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group.
  • R 1 is a C1 to C10 alkoxy group, or a C1 to C10 alkyl group,
  • R 2 is a hydrogen atom, or a C1 to C10 alkyl group
  • R 3 may be a nitro group or a C1 to C10 alkoxy group.
  • the compound represented by Structural Formula 1 may be represented by Structural Formula 2 or 3 below.
  • R 1 is a C1 to C10 alkoxy group, or a C1 to C10 alkyl group,
  • R 2 is a hydrogen atom, or a C1 to C10 alkyl group
  • R 3 is a nitro group or a C1 to C10 alkoxy group.
  • the compound represented by Structural Formula 1 may be the following compound 1 or compound 2.
  • any isomers and mixtures thereof are also included in the compounds of Structural Formulas 1, 2 or 3 .
  • the compound of formula (2) has optical isomers
  • the optical isomers resolved from the racemate are also included in the compound of formula (2).
  • Their isomers can be obtained as individual single products according to synthetic and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • the pharmaceutical composition for preventing or treating cancer diseases of the present invention includes the following compound 1 or compound 2, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition for preventing or treating cancer diseases may further include a topoisomerase inhibitor.
  • the topoisomerase inhibitor is preferably at least one selected from irinotecan, topotecan, and belotecan, and more preferably irinotecan.
  • the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, lung cancer, pancreatic cancer, basal cell cancer, brain cancer, liver cancer, and breast cancer, but the scope of the present invention is not limited thereto.
  • the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer and lung cancer.
  • the pharmaceutical composition for preventing or treating cancer is characterized in that it is for inhibiting hedgehog signaling.
  • inhibition of hedgehog signaling may be implemented according to inhibition of GLI transcriptional activity.
  • the pharmaceutical composition of the present invention may be prepared using pharmaceutically acceptable and physiologically acceptable adjuvants in addition to the active ingredient, and the adjuvant includes an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, and a lubricant. agent or flavoring agent, etc. may be used.
  • the pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above for administration.
  • Formulations of the pharmaceutical composition may be solutions, syrups, juices, suspensions, emulsions, drops, or the like.
  • suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture.
  • suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the pharmaceutical composition of the present invention is preferably administered by transdermal administration.
  • the screening method for cancer disease prevention or treatment compounds of the present invention is a GLI reporter NIH3t3 cell line N,N'-1,3-phenylene dibenzamide (N,N'-1,3-phenylene dibenzamide)-based compound library processing step.
  • the GLI reporter NIH3t3 cell line may include a luciferase gene that is controlled according to the expression level of GLI.
  • compounds having an IC50 value of 15 ⁇ M or less for reporter activity are preferably screened for, more preferably 13 ⁇ M or less, and still more preferably 11 ⁇ M or less can be screened.
  • the screened compound may include the following compound 1 and compound 2.
  • the GLI transcription inhibitory IC50 value was measured and the value of the compound 1 and compound 2 was low. was screened.
  • a GLI luciferase assay was performed to determine the degree of inhibition of GLI transcriptional activity for the compounds in the library.
  • 2.5x10 4 NIH3t3-GLI luciferase cells were seeded in a 96-well plate, and 7 hours later, 1 ⁇ M N-SHH peptide as a ligand was treated. After overnight treatment with the compounds at different concentrations (0-50 ⁇ M), 7 hours later, the ability to inhibit GLI transcriptional activity was confirmed using a luciferase kit, and the results are shown in FIG. 2 .
  • the GLI transcriptional inhibition IC50 value was not measured up to a concentration of 50 ⁇ M, and the IC50 values of Compound 1 and Compound 2 were 10.04 ⁇ M and 10.15 ⁇ M, respectively, indicating that the inhibitory ability was very excellent.
  • colon cancer cells were seeded to confirm the hedgehog / GLI protein level of normal colorectal cells (CCD-18Co) and colorectal cancer cell lines (DLD-1, HT29, HCT116). Then, the next day, lysate (cell lysate), Western blotting was performed, and the expression of GLI1 was confirmed. The results are shown in FIG. 3 .
  • GLI1 was low in CCD-18Co, a normal colon cell, and DLD-1, a colorectal cancer cell line, and the expression of GLI1 was high in the HCT116 and HT29 colon cancer cell lines.
  • normal colorectal cells CCD-18Co
  • colorectal cancer cell lines DLD-1, HT29, HCT116
  • compound 1 10 ⁇ M or 20 ⁇ M
  • IRI 10 ⁇ M or 20 ⁇ M
  • the WST-1 solution was added and the absorbance was measured at 450 nm after reaction for 3 hours to confirm cell growth, and the results are shown in FIG. 5 .
  • Compound 1 and irinotecan were co-treated, there was no effect in colonic normal cells, and no significant cell growth inhibition effect was observed in DLD-1 cells with low GLI1 expression.
  • HCT116 and HT29 cells with high GLI1 expression cell growth was significantly significantly reduced when the two components were treated in combination rather than treated alone.
  • a caspase inhibitor 24 hours after seeding colorectal cancer cell line HT29 cells After 30 minutes of pretreatment with -fmk, 10 ⁇ M of compound 1 was treated, and 10 ⁇ M of IRI was treated in combination after 1 hour. After 24 hours, cells were obtained and Western blotting was performed to analyze the expression of apoptosis protein, and the results are shown in FIG. 9 . According to this, it was confirmed that apoptosis was inhibited in the group treated with Compound 1 and IRI together with a Casspace inhibitor, resulting in Casspace-dependent apoptosis.
  • compound 1 a hedgehog/GLI inhibitor, enhances the efficacy of IRI, an anticancer drug
  • compound 1 was treated by concentration (0, 10, 20 ⁇ M) to determine apoptosis-related proteins DR5, DR4, Bim, Noxa, Puma , Bid, Bcl-xL, XIAP, and the expression of Survivin was confirmed by Westing blotting, and the results are shown in FIG. 12 . According to this, it was confirmed that the death receptor (death receptor) DR5, which is a receptor mediating apoptosis, is increased by the treatment of compound 1. That is, it can be seen that Compound 1 increases DR5 to increase the apoptosis efficacy of IRI.
  • DR5 death receptor
  • the novel compound of N,N'-1,3-phenylene dibenzamide represented by Structural Formula 1 of the present invention targets GLI in the Hedgehog signaling pathway.
  • GLI in the Hedgehog signaling pathway.
  • compound 1 or compound 2 with high GLI transcriptional activity inhibition ability screened from the N,N'-1,3-phenylene dibenzamide-based compound library of the present invention is It is useful for preventing or treating cancer diseases, and in particular, it can exhibit a synergistic effect in preventing or treating cancer diseases by using it in combination with a topoisomerase inhibitor.

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Abstract

La présente invention concerne un nouveau composé représenté par la formule développée 1. La présente invention peut finalement inhiber une voie de transmission de signal hedgehog par commande de l'expression et de l'activation de GLI par ciblage de celle-ci dans la voie de transmission de signal hedgehog, et peut en outre améliorer l'inhibition de l'expression et de l'activation de GLI au moyen d'une utilisation concomitante avec un inhibiteur de la topoisomérase. Le composé criblé à partir d'une bibliothèque comprenant les nouveaux composés peut être utilisé pour prévenir ou traiter des maladies cancéreuses.
PCT/KR2021/005808 2020-05-29 2021-05-10 Composé de dibenzamide phénylène et composition pharmaceutique pour prévenir ou traiter des maladies cancéreuses le comprenant en tant que principe actif Ceased WO2021241913A1 (fr)

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KR1020210048315A KR102709756B1 (ko) 2020-05-29 2021-04-14 페닐렌 디벤즈아미드계 화합물 및 이를 유효성분으로 포함하는 암질환 예방 또는 치료용 약제학적 조성물

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50105558A (fr) * 1973-12-19 1975-08-20
WO2004032716A2 (fr) * 2002-10-08 2004-04-22 Massachusetts Institute Of Technology Composes pour la modulation du transport du cholesterol
WO2005033288A2 (fr) * 2003-09-29 2005-04-14 The Johns Hopkins University Antagonistes de la voie hedgehog
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