WO2022177290A1 - 항암제 내성 치료용 조성물 - Google Patents
항암제 내성 치료용 조성물 Download PDFInfo
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- WO2022177290A1 WO2022177290A1 PCT/KR2022/002290 KR2022002290W WO2022177290A1 WO 2022177290 A1 WO2022177290 A1 WO 2022177290A1 KR 2022002290 W KR2022002290 W KR 2022002290W WO 2022177290 A1 WO2022177290 A1 WO 2022177290A1
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- cancer
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- anticancer agent
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
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Definitions
- the present invention relates to a composition capable of enhancing sensitivity to an anticancer agent, overcoming resistance to an anticancer agent, or further inhibiting the growth of resistant cancer.
- Cancer is a very lethal disease that can threaten the life of an individual by abnormally and unrestrictedly proliferating the cells constituting the tissue to form a tumor, thereby preventing the organs from performing their normal functions.
- malignant neoplasm cancer
- GC gastric cancer
- the present inventors have developed a combination agent for anticancer drug resistance treatment that can effectively treat malignant gastric cancer by overcoming anticancer drug resistance.
- One object of the present invention is to provide a pharmaceutical composition for treating anticancer drug resistance and a method for treating anticancer drug resistance.
- Another object of the present invention is to provide a pharmaceutical composition for enhancing the anticancer drug sensitivity and a method for enhancing the anticancer drug sensitivity.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating anticancer drug-resistant cancer and a method for preventing or treating anticancer drug-resistant cancer.
- Another object of the present invention is to provide a screening method of a composition for the treatment of anticancer drug resistance.
- the present invention relates to a pharmaceutical composition for overcoming resistance to anticancer drugs.
- the composition may include MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) as an active ingredient.
- MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- the MRTF A inhibitor may include a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- R 1 is a 5- to 6-membered ring heteroaryl
- R 2 to R 4 may each independently be hydrogen or halogen
- the heteroaryl may be furan or pyridine.
- the MRTF A inhibitor of the present invention performs a function of inhibiting Rho / MRTF / SRF signal, and the compound represented by Formula 1 may be at least one selected from the group consisting of CCG-232601, CCG-203971 and CCG-222740. However, if it corresponds to the type of inhibitor performing the same function, it is not limited thereto.
- CCG-232601 is a compound in which R 1 in Formula 1 is pyridine, R 2 and R 3 are fluorine, and R 4 is chloride, N-(4-chlorophenyl)-5 ,5-difluoro-1-(3-(pyridin-4-yl)benzoyl)piperidine-3-carboxamide [N-(4-Chlorophenyl)-5,5-difluoro-1-(3- (pyridin-4-yl)benzoyl)piperidine-3-carboxamide] and may be a compound represented by the following formula (2).
- the CCG-232601 compound of the present invention is an inhibitor of the Rho/MRTF/SRF signal transduction pathway and is known as a potential antifibrotic therapeutic agent for systemic scleroderma. It corresponds to a known substance.
- CCG-203971 is a compound in which R 1 in Formula 1 is furan, R 2 and R 3 are hydrogen, R 4 is chloride, and N-(4-chlorophenyl)-1 -(3-(furan-2-yl)benzoyl)piperidine-3-carboxamide [N-(4-Chlorophenyl)-1-(3-(furan-2-yl)benzoyl)piperidine-3-carboxamide ] may be a compound represented by the following formula (3).
- the CCG-203971 compound of the present invention is known to play a role in metastasis of melanoma and breast cancer as an inhibitor of the Rho/MKL1/SRF transcription pathway and is clinically associated with prostate cancer.
- the CCG-222740 is a compound in which R 1 in Formula 1 is furan, R 2 and R 3 are fluorine, and R 4 is chloride, N-(4-chlorophenyl)- 5,5-difluoro-1-(3-(furan-2-yl)benzoyl)piperidine-3-carboxamide[N-(4-Chlorophenyl)-5,5-difluoro-1-(3 -(furan-2-yl)benzoyl)piperidine-3-carboxamide] and may be a compound represented by the following formula (4).
- the CCG-222740 compound of the present invention is an MRTF/SRF inhibitor that prevents the expression of alpha smooth muscle actin protein and has low cytotoxicity, and corresponds to a substance known to effectively prevent scar tissue formation in a preclinical model of fibrosis.
- the compounds represented by Formulas 1 to 4 of the present invention can very effectively treat anticancer drug resistance.
- the composition of the present invention can be very effectively used for the prevention, improvement or treatment of cancer by overcoming the anticancer drug resistance of stem-like malignant cancer.
- the pharmaceutically acceptable salts of the present invention may include addition salts of acids or bases, and stereochemical isomers thereof.
- the compound may be in the form of an addition salt of an organic or inorganic acid. Salts have a desirable effect in a patient when administered to a patient, and include, but are not particularly limited to, any salts that retain the activity of their parent compound.
- salts include inorganic and organic salts such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, Benzoic acid, stearic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idet, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, fumaric acid, gluceptic acid, ecylline Acid, pamoic acid, gluconic acid, methyl nitric acid, malonic acid, hydrochloric acid, hydroiodic acid, hydroxynaphtolic acid, isethionic acid, lactobi
- Addition salts of bases include salts of alkali metals or alkaline earth metals, such as salts of ammonium, lithium, sodium, potassium, magnesium, calcium and the like; salts with organic bases, such as salts of benzathine, N-methyl-D-glucamine, hydrabamine and the like; and salts with amino acids, such as arginine, lysine, and the like.
- these salts can be converted to their free form by treatment with an appropriate base or acid.
- the term "anticancer drug resistance” refers to a decrease in the effect of the corresponding drug when the anticancer drug is used quantitatively and repeatedly. It is a condition in which the same effect as before is not obtained even if the dose must be increased or the same dose of the substance is administered.
- the term "overcoming resistance (resistance treatment)” means that when an anticancer agent is used quantitatively and repeatedly, the effect of the drug is reduced, or in order to obtain the same effect previously experienced in patients with anticancer drug resistance, increase or use the amount It refers to the action of restoring a state in which the frequency must be increased or the same effect as before is not obtained even when the same dose of a substance is administered. More specifically, the same anticancer effect can be obtained even if the anticancer agent is applied fewer times or a smaller dose, or the same effect can be obtained even if the same dose or a lower dose of the substance is administered by returning to the state prior to the occurrence of anticancer drug resistance. action that makes it exist.
- the anticancer agent that induces resistance as described above is a drug having a mechanism to kill cancer cells, and corresponds to a drug having an anticancer effect, and refers to a drug having a cancer treatment effect.
- the type is not particularly limited, for example, cisplatin, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cetuximab, viscumalbum, asparaginase, tretinoin , hydroxycarbamide, dasatinib, estramustine, gemtuzuma
- the term “cancer” refers to or refers to a physiological condition typically characterized by unregulated cell growth in mammals.
- the cancer is gastric cancer, thyroid cancer, parathyroid cancer, ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, blood cancer , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, CNS
- the pharmaceutical composition for overcoming resistance to the anticancer agent may further include another anticancer agent, thereby remarkably improving the effect of overcoming resistance.
- the type of anticancer agent that may be further included is not particularly limited, but for example, cisplatin, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib , nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cetuximab, Viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogam
- the compounds represented by Formulas 1 to 4 induce growth inhibition and apoptosis of cancer or cancer stem cells by overcoming anticancer drug resistance when administered in combination with a general anticancer agent, more preferably a platinum-based anticancer agent. It can give a very high synergistic effect.
- the "combination administration" may be achieved by administering the individual components of a treatment regimen simultaneously, sequentially, or separately.
- the combination therapy is not limited thereto , defined as being able to provide a synergistic effect while being therapeutically superior to the efficacy that can be obtained by administering one or the other of the components of the combination therapy at conventional doses, as measured through the period to disease progression or survival.
- the compound represented by any one of Formulas 1 to 4 and the anticancer agent may be included in a weight ratio of 1: 0.01 to 100 or 1: 0.1 to 400, but is not limited thereto. It can be appropriately adjusted according to the type.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with the use of the anticancer agent for overcoming resistance, more preferably 12 to 36 hours before the use of the anticancer agent, most preferably 18 to 30 hours before the use of the anticancer agent may be administered. If the content is out of the above range, the effect of overcoming the resistance of anticancer drugs due to co-administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and the platinum-based anticancer agent may be included in a weight ratio of 1:0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with the use of the platinum-based anticancer agent for overcoming resistance, more preferably 12 to 36 hours before the use of the platinum-based anticancer agent, most preferably may be administered 18 to 30 hours before. If the content is out of the above range, the effect of overcoming the resistance of the desired anticancer agent due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and cisplatin may be included in a weight ratio of 1: 0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or at the same time as cisplatin for overcoming resistance, more preferably 12 to 36 hours before using cisplatin, most preferably 18 to 30 hours before using cisplatin may be administered. If the content is out of the above range, the effect of overcoming the resistance of the desired anticancer agent due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and oxaliplatin may be included in a weight ratio of 1: 0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with oxaliplatin for overcoming resistance, more preferably 12 to 36 hours before using oxaliplatin, and most preferably 18 to 30 hours before using oxaliplatin. may be administered. If the content is out of the above range, the effect of overcoming the resistance of the desired anticancer agent due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- composition of the present invention is an agent for reducing the activity or expression level of MRTF A (Myocardin-related transcription factor A) protein; Alternatively, it may include an agent that reduces the expression level of the gene encoding the protein as an active ingredient.
- MRTF A Myocardin-related transcription factor A
- the agent for reducing the activity or expression level of the protein of the present invention is any one selected from the group consisting of compounds, peptides, peptide mimetics, aptamers, antibodies, and natural products that specifically bind to the protein or a portion thereof. It may include the above, but is not limited thereto, and is known as a method commonly used in the art as it corresponds to a means for deriving an effect of inhibiting its activity or expression by acting directly or indirectly on the target MRTF A protein. It is not limited thereto, and may include all of them as long as they can be easily derived by the described technology.
- the "peptide mimetics (Peptide Minetics)" is a peptide or non-peptide that inhibits the binding domain of the MRTF A protein leading to inhibition of MRTF A activity.
- Major residues of non-hydrolyzable peptide analogs include the ⁇ -turn dipeptide core (Nagai et al. Tetrahedron Lett 26:647, 1985), keto-methylene pseudopeptides (Ewenson et al. J Med chem 29:295, 1986; and Ewenson et al. in Peptides: Structure and Function (Proceedings of the 9th AmeriCan Peptide Symposium) Pierce chemiCal co.
- the "aptamer (Aptamer)" is a single-stranded nucleic acid (DNA, RNA or modified nucleic acid) having a stable tertiary structure by itself and having a characteristic capable of binding to a target molecule with high affinity and specificity.
- SELEX Systematic Evolution of Ligands by EXponential enrichment
- Many aptamers capable of binding to various target molecules have been continuously discovered. Aptamers are comparable to single antibodies because of their inherent high affinity (usually at pM level) and specificity to bind to a target molecule, and in particular, have high potential as an alternative antibody to be referred to as a “chemical antibody”.
- the "antibody” can be used either prepared through the protein injection or purchased commercially.
- the antibody includes polyclonal antibodies, monoclonal antibodies, and fragments capable of binding to an epitope.
- the polyclonal antibody can be produced by a conventional method of injecting the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody.
- Such polyclonal antibodies can be purified by any method known in the art, and can be made from any animal species host, such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like.
- the monoclonal antibody can be prepared using any technique that provides for the production of antibody molecules through culturing of continuous cell lines.
- Such techniques include, but are not limited to, hybridoma technology, human B-cell line hybridoma technology, and EBV-hybridoma technology.
- antibody fragments containing specific binding sites for the above proteins can be prepared.
- the F(ab')2 fragment may be prepared by digesting an antibody molecule with pepsin, and the Fab fragment may be prepared by reducing the disulfide bridge of the F(ab')2 fragment.
- the Fab expression library small, monoclonal Fab fragments having a desired specificity can be quickly and conveniently identified.
- the antibody may be bound to a solid substrate to facilitate subsequent steps such as washing or separation of the complex.
- Solid substrates include, for example, synthetic resins, nitrocellulose, glass substrates, metal substrates, glass fibers, microspheres and microbeads.
- the synthetic resin includes polyester, polyvinyl chloride, polystyrene, polypropylene, PVDF and nylon.
- the agent for reducing the expression level of the gene encoding the protein of the present invention is a gene encoding the protein, preferably an antisense nucleotide, a small interfering RNA that complementarily binds to the gene or a portion thereof; siRNA), short hairpin RNA, and ribozyme may be one or more selected from the group consisting of, but not limited thereto, directly or indirectly to the gene encoding the target MRTF A protein. It corresponds to a means for deriving the effect that the expression is inhibited by acting, and as long as it can be easily derived by a method known in the art as a method commonly used in the art, it is not limited thereto, and may include all.
- the agent for reducing the expression level of the gene encoding the MRTF A protein is an antisense nucleotide complementary to a polynucleotide consisting of a nucleotide sequence that is part or all of the gene encoding the MRTF A protein, small interference RNA (short interfering RNA; siRNA), short hairpin RNA (short hairpin RNA), and may include any one or more selected from the group consisting of ribozyme (ribozyme), but is not limited thereto.
- siRNA small interference RNA
- siRNA short hairpin RNA
- ribozyme ribozyme
- the "antisense nucleotide” binds (hybridizes) to the complementary nucleotide sequence of DNA, immature-mRNA, or mature mRNA as defined in Watson-Click base pairing to interfere with the flow of genetic information from DNA to protein will be.
- the nature of antisense nucleotides specific to a target sequence makes them exceptionally versatile. Since antisense nucleotides are long chains of monomeric units, they can be readily synthesized for the target RNA sequence. Many recent studies have demonstrated the usefulness of antisense nucleotides as biochemical means to study target proteins.
- antisense nucleotides Due to recent advances in oligonucleotide chemistry and nucleotide synthesis with improved cell line adsorption, target binding affinity and nuclease resistance, the use of antisense nucleotides can be considered as a new type of inhibitor.
- the shRNA and “siRNA” are nucleic acid molecules capable of mediating RNA interference or gene silencing, and because they can inhibit the expression of a target gene, an efficient gene knockdown method or gene therapy used in a way
- the shRNA forms a hairpin structure by bonding between complementary sequences within a single-stranded oligonucleotide.
- siRNA which is a double-stranded oligonucleotide, and can inhibit expression by specifically binding to mRNA having a complementary sequence.
- siRNA refers to a small double-stranded RNA fragment of 21 to 25 nucleotides in size that modifies the target mRNA by double-stranded RNA (dsRNA) to induce RNA interference (RNAi).
- siRNA which means of the shRNA and siRNA to be used can be determined by a person skilled in the art, and if the mRNA sequences they target are the same, a similar expression reduction effect can be expected.
- it specifically acts on the gene encoding the MRTF A to cut the gene (eg, mRNA molecule) of MRTF A to induce RNA interference (RNAi, RNA interference) phenomenon, thereby reducing the expression of MRTF A.
- RNAi RNA interference
- siRNA can be synthesized chemically or enzymatically.
- the method for preparing siRNA is not particularly limited, and methods known in the art may be used.
- a method of directly chemically synthesizing siRNA a method of synthesizing siRNA using in vitro transcription, a method of cleaving a long double-stranded RNA synthesized by in vitro transcription using an enzyme
- Expression method through intracellular delivery of an shRNA expression plasmid or viral vector and expression method through intracellular delivery of a PCR (polymerase chain reaction)-induced siRNA expression cassette (cassette), but are not limited thereto.
- the "ribozyme” refers to an RNA molecule having catalytic activity. Ribozymes having various activities are known, ribozymes of the MRTF A gene include known or artificially generated ribozymes, and selectively ribozymes having target-specific RNA cleavage activity are prepared by known standard techniques. can be manufactured.
- it relates to a pharmaceutical composition for enhancing anticancer drug sensitivity.
- the composition may include MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) as an active ingredient.
- MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- the MRTF A inhibitor may include a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- R 1 is a 5- to 6-membered ring heteroaryl
- R 2 to R 4 may each independently be hydrogen or halogen
- the heteroaryl may be furan or pyridine.
- the MRTF A inhibitor of the present invention performs a function of inhibiting Rho / MRTF / SRF signal, and the compound represented by Formula 1 may be at least one selected from the group consisting of CCG-232601, CCG-203971 and CCG-222740. However, if it corresponds to the type of inhibitor performing the same function, it is not limited thereto.
- the MRTF A inhibitor is preferably at least one selected from the group consisting of CCG-232601, CCG-203971 and CCG-222740, and the MRTF A inhibitor, CCG-232601, CCG-203971 and CCG-222740; Descriptions of pharmaceutically acceptable salts, anticancer agents, etc. are the same as those described in the pharmaceutical composition for anticancer drug resistance treatment, and thus are omitted to avoid excessive complexity of the present specification.
- the compounds represented by Formulas 1 to 4 of the present invention can effectively enhance the sensitivity of anticancer agents, and more specifically, by increasing the drug reactivity of anticancer agents to effectively increase the anticancer action of anticancer agents, they are very effective in preventing, improving or treating cancer. can be used
- the "anti-cancer drug sensitivity” refers to the response sensitivity to the use of an anti-cancer agent, and refers to a characteristic that can maximize the effect on the subject when the anti-cancer agent is administered.
- increasing the anticancer drug sensitivity it is possible to increase the therapeutic effect of the anticancer drug by allowing the drug effect to work smoothly.
- the pharmaceutical composition for enhancing sensitivity to anticancer agents may further include other anticancer agents, thereby remarkably improving the effect of enhancing sensitivity.
- the type of anticancer agent that may be further included is not particularly limited, but for example, cisplatin, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib , nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cetuximab, Viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozo
- the compounds represented by Formulas 1 to 4 induce growth inhibition and apoptosis of cancer or cancer stem cells by enhancing anticancer drug sensitivity when administered in combination with a general anticancer agent, more preferably a platinum-based anticancer agent. It can give a very high synergistic effect.
- the compound represented by any one of Formulas 1 to 4 and the anticancer agent may be included in a weight ratio of 1: 0.01 to 100 or 1: 0.1 to 400, but is not limited thereto. It can be appropriately adjusted according to the type.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with the use of the anticancer agent for sensitivity enhancement, more preferably 12 to 36 hours before the use of the anticancer agent, most preferably 18 to 30 hours before the use of the anticancer agent may be administered. If the content is out of the above range, the effect of enhancing anticancer drug sensitivity due to co-administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target subject.
- the compound represented by any one of Formulas 1 to 4 and the platinum-based anticancer agent may be included in a weight ratio of 1:0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with the use of the platinum-based anticancer agent for sensitivity enhancement, more preferably 12 to 36 hours before the use of the platinum-based anticancer agent, most preferably may be administered 18 to 30 hours before.
- the content is out of the range, the effect of enhancing the desired anticancer drug sensitivity due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target subject.
- the compound represented by any one of Formulas 1 to 4 and cisplatin may be included in a weight ratio of 1: 0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with cisplatin for sensitivity enhancement, more preferably 12 to 36 hours before using cisplatin, and most preferably 18 to 30 hours before using cisplatin. may be administered.
- the content is out of the range, the effect of enhancing the desired anticancer drug sensitivity due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target subject.
- the compound represented by any one of Formulas 1 to 4 and oxaliplatin may be included in a weight ratio of 1: 0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with oxaliplatin for overcoming resistance, more preferably 12 to 36 hours before using oxaliplatin, and most preferably 18 to 30 hours before using oxaliplatin. may be administered. If the content is out of the above range, the effect of overcoming the resistance of the desired anticancer agent due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- composition of the present invention is an agent for reducing the activity or expression level of MRTF A (Myocardin-related transcription factor A) protein; Alternatively, it may include an agent that reduces the expression level of the gene encoding the protein as an active ingredient.
- MRTF A Myocardin-related transcription factor A
- it relates to a pharmaceutical composition for preventing or treating anticancer drug-resistant cancer.
- the composition may include MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) as an active ingredient.
- MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- the MRTF A inhibitor may include a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- R 1 is a 5- to 6-membered ring heteroaryl
- R 2 to R 4 may each independently be hydrogen or halogen
- the heteroaryl may be furan or pyridine.
- the MRTF A inhibitor of the present invention performs a function of inhibiting Rho / MRTF / SRF signal, and the compound represented by Formula 1 may be at least one selected from the group consisting of CCG-232601, CCG-203971 and CCG-222740. However, if it corresponds to the type of inhibitor performing the same function, it is not limited thereto.
- the MRTF A inhibitor is preferably at least one selected from the group consisting of CCG-232601, CCG-203971 and CCG-222740, and the MRTF A inhibitor, CCG-232601, CCG-203971 and CCG-222740; Descriptions of pharmaceutically acceptable salts, anticancer agents, etc. are the same as those described in the pharmaceutical composition for anticancer drug resistance treatment, and thus are omitted to avoid excessive complexity of the present specification.
- the compounds represented by Chemical Formulas 1 to 4 of the present invention can very effectively treat anticancer drug-resistant cancer with anticancer drug resistance.
- the composition of the present invention can be used very effectively for the prevention, improvement or treatment of cancer by lowering the anticancer drug resistance of stem-like malignant cancer and at the same time increasing the anticancer drug sensitivity.
- the pharmaceutical composition for the prevention or treatment of anticancer drug-resistant cancer further includes an anticancer agent, thereby significantly improving the growth inhibition efficiency of cancer stem cells inducing resistance to anticancer agent, preventing or treating anticancer drug-resistant cancer The effect can also be improved.
- anticancer agent further included as described above of the present invention is not particularly limited, but for example, cisplatin, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib , vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, bevacizumab, cetux Simab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tusetan, heptaplatin, methylaminolevulinic acid, amsacrine
- the compounds represented by Formulas 1 to 4 induce growth inhibition and apoptosis of anticancer drug-resistant cancer or cancer stem cells when administered in combination with a general anticancer agent, more preferably a platinum-based anticancer agent. It can give a very high synergistic effect.
- the compound represented by any one of Formulas 1 to 4 and the anticancer agent may be included in a weight ratio of 1: 0.01 to 100 or 1: 0.1 to 400), but is not limited thereto. It can be appropriately adjusted according to the type of In addition, the compounds represented by Chemical Formulas 1 to 4 may be administered before or simultaneously with the use of the anticancer agent, more preferably 12 to 36 hours before the use of the anticancer agent, most preferably 18 to 30 hours before the use of the anticancer agent. have. If the content is out of the above range, there is a problem that the therapeutic effect of anticancer drug-resistant cancer cannot be obtained due to the combined administration, and toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and the platinum-based anticancer agent may be included in a weight ratio of 1:0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with the use of the platinum-based anticancer agent, more preferably 12 to 36 hours before use of the platinum-based anticancer agent, most preferably 18 to 30 It may be administered before time.
- the desired therapeutic effect of anticancer drug-resistant cancer cannot be obtained due to the combined administration, and there is a problem that toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and cisplatin may be included in a weight ratio of 1:0.1 to 10), but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or at the same time as cisplatin, more preferably 12 to 36 hours before cisplatin, and most preferably 18 to 30 hours before using cisplatin. have.
- the desired therapeutic effect of anticancer drug-resistant cancer cannot be obtained due to the combined administration, and there is a problem that toxicity by the drug may occur in the target individual.
- the compound represented by any one of Formulas 1 to 4 and oxaliplatin may be included in a weight ratio of 1: 0.1 to 10, but is not limited thereto.
- the compounds represented by Formulas 1 to 4 may be administered before or simultaneously with oxaliplatin for overcoming resistance, more preferably 12 to 36 hours before using oxaliplatin, and most preferably 18 to 30 hours before using oxaliplatin. may be administered. If the content is out of the above range, the effect of overcoming the resistance of the desired anticancer agent due to the combined administration cannot be obtained, and there is a problem that toxicity by the drug may occur in the target individual.
- composition of the present invention is an agent for reducing the activity or expression level of MRTF A (Myocardin-related transcription factor A) protein; Alternatively, it may include an agent that reduces the expression level of the gene encoding the protein as an active ingredient.
- MRTF A Myocardin-related transcription factor A
- the disease to be prevented, improved, or treated in the composition of the present invention may be an anticancer drug-resistant cancer that has occurred or is likely to be developed in a target individual.
- the "target subject” refers to mammals including humans, for example, humans, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and preferably may be a human, but is not limited thereto.
- the term “human” refers to a person who has or is suspected of having cancer, and may mean a patient in need or expected to treat cancer, but is not limited thereto.
- the "prevention" of the present invention may include, without limitation, any act of blocking or suppressing or delaying symptoms caused by uncontrolled growth of cancer cells using the composition of the present invention.
- the “improvement” of the present invention may include, without limitation, any action in which symptoms caused by uncontrolled growth of cancer cells, etc. are improved or beneficial by using the composition of the present invention.
- treatment of the present invention may be included without limitation as long as the symptoms caused by the uncontrolled growth of cancer cells are improved or beneficial by using the composition of the present invention.
- the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is intended for humans.
- the pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, pain-freezing agents
- a topical agent, solubilizer, isotonic agent, stabilizer, etc. may be mixed and used.
- a base, excipient, lubricant, preservative, etc. may be used for topical administration.
- the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier for example, in the case of oral administration, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. can be prepared in the form of, and in the case of injection, it can be prepared in the form of unit dose ampoules or multiple doses. have.
- it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
- the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
- parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
- the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
- the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day It may be administered at /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
- the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
- it relates to a method of treating anticancer drug resistance or enhancing anticancer drug sensitivity.
- An example of the method of the present invention may include administering an effective amount of an MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) to a subject in need of administration.
- an MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- an agent for reducing the activity or expression level of MRTF A protein to a subject in need of administration may include the step of administering an effective amount of an agent that reduces the expression level of the gene encoding the protein.
- it relates to a method of treating anticancer drug resistance or enhancing anticancer drug sensitivity.
- An example of the method of the present invention may include administering an effective amount of an MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) to a subject in need of administration.
- an MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- an agent for reducing the activity or expression level of MRTF A protein to a subject in need of administration may include the step of administering an effective amount of an agent that reduces the expression level of the gene encoding the protein.
- it relates to a method of treating anticancer drug resistance or enhancing anticancer drug sensitivity.
- An example of the method of the present invention may include administering an effective amount of an MRTF A inhibitor (Myocardin-related transcription factor A inhibitor) to a subject in need of administration.
- an MRTF A inhibitor Myocardin-related transcription factor A inhibitor
- an agent for reducing the activity or expression level of MRTF A protein to a subject in need of administration may include the step of administering an effective amount of an agent that reduces the expression level of the gene encoding the protein.
- the anticancer drug resistance treatment method of the present invention a method for enhancing anticancer drug sensitivity; And in the method for preventing or treating anticancer drug-resistant cancer, MRTF A inhibitor, each protein or a gene encoding the same, an agent that reduces the activity or expression level of the protein; Or the description of the agent for reducing the expression level of the gene encoding the protein is the same as described in the composition for overcoming anticancer drug resistance, and is omitted in order to avoid excessive complexity of the present specification.
- administration means providing a predetermined composition of the present invention to a subject by any suitable method.
- the "subject" in need of such administration may include both mammals and non-mammals.
- mammals include humans, non-human primates such as chimpanzees, other apes or monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs or cats; laboratory animals such as rodents such as rats, mice or guinea pigs, but are not limited thereto.
- non-mammal in the present invention may include, but are not limited to, birds or fish.
- the formulation of the composition administered as described above in the present invention is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and a liquid formulation for oral or parenteral administration immediately before use. It may be administered in a solid form preparation intended to be converted into However, the present invention is not limited thereto.
- a pharmaceutically acceptable carrier may be additionally administered together with the composition of the present invention.
- the pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc.
- a buffer Preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc.
- bases, excipients, lubricants, preservatives, etc. can be used for topical administration.
- the formulation of the compound of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier for example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
- it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
- the route of administration of the composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or work. Oral or parenteral administration is preferred.
- parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
- a "pharmaceutically effective amount” refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system.
- an “effective amount” for therapeutic use is the amount of a composition disclosed herein required to provide a clinically significant reduction in disease.
- An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to the amount in which the active substance has a therapeutic effect.
- the active substance is an anti-cancer drug-resistant therapeutic agent and a preventive, ameliorating or therapeutic agent for anti-cancer drug-resistant cancer.
- composition of the present invention may vary depending on various factors including the activity of the active substance used, age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
- the dosage of the active substance may vary depending on the patient's condition, body weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and may be 0.0001 to 100 mg/kg or 0.001 per day. to 100 mg/kg may be administered. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
- the compounds according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
- the active substances of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
- composition of the present invention may be used in combination with other anticancer agents, wherein the anticancer agents include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vande tanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, Cisplatin, cetuximab, viscumalbum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tucetan, heptaplatin, methylamino
- the present invention relates to a screening method of a composition for the treatment of anticancer drug resistance.
- the method of the present invention comprises the steps of contacting a candidate material with a biological sample containing MRTF A (Myocardin-related transcription factor A) or a cell expressing the same; and measuring the activity or expression level of the MRTF A protein or a gene encoding the same.
- MRTF A Myocardin-related transcription factor A
- the candidate substance when the activity or expression level of the MRTF A protein or a gene encoding it measured above is decreased, the candidate substance may be determined as a composition for treating anticancer drug resistance.
- the "screening” refers to selecting a substance having a specific target property from a candidate group consisting of several substances by a specific manipulation or evaluation method.
- the cell may be engineered to overexpress the MRTF A protein or a gene encoding the same, preferably transfected by introducing a recombinant vector containing the gene encoding the protein into the cell.
- the composition according to the present invention can suppress the growth of anticancer drug-resistant cancer by overcoming anticancer drug resistance or enhance anticancer drug sensitivity, and when administered in combination with anticancer agent, prevent various cancers, particularly anticancer drug-resistant cancer, It can be used very effectively for improvement or treatment.
- FIG. 1 is a cancer cell line and a cell line having cancer stem cell characteristics according to an embodiment of the present invention when cisplatin (CDDP) or CCG-232601 treatment, the survival and growth inhibitory effect of the cell viability measurement method showing the results to be.
- CDDP cisplatin
- CCG-232601 CCG-232601
- Figure 2 shows the results of measuring oxygen consumption (OCR) and extracellular matrix oxidation (ECAR) of cells after treatment with CCG-232601 in HS746T and MKN1 cell lines having cancer stem cell characteristics according to an embodiment of the present invention; it is do
- FIG. 3 is a diagram showing the results of confirming the cancer metastasis inhibitory effect upon CCG-232601 treatment on HS746T and MKN1 cell lines having cancer stem cell characteristics according to an embodiment of the present invention.
- FIG. 4 is a diagram showing the results of confirming drug reactivity when cisplatin treatment in HS746T and MKN1 cell lines according to an embodiment of the present invention.
- FIG. 5 is a diagram showing a schematic diagram of the combined treatment of CCG-232601 and cisplatin in the MKN1 cell line according to an embodiment of the present invention.
- Cell Counting Kit-8 Cell Counting Kit-8; CCK-88 for the survival and growth inhibitory effects when CCG-232601 and oxaliplatin are treated alone or in combination in the HS746T cell line according to an embodiment of the present invention.
- Cell viability analysis kit 8 is a cell viability analysis kit (Cell Counting Kit-8; CCK-8) when CCG-232601, CCG-203971 or CCG-222740 and cisplatin are combined in HS746T cell line according to an embodiment of the present invention using cisplatin; It is a diagram showing the results of confirming the resistance treatment effect.
- a pharmaceutical composition for the treatment of anticancer drug resistance comprising a Myocardin-related transcription factor A (MRTF A) inhibitor.
- MRTF A Myocardin-related transcription factor A
- a pharmaceutical composition for enhancing anticancer drug sensitivity comprising an MRTF A inhibitor.
- Another embodiment of the present invention relates to a method for treating anticancer drug resistance or enhancing anticancer drug sensitivity, comprising administering an effective amount of an MRTF A inhibitor to a subject in need of administration.
- Another embodiment of the present invention relates to a pharmaceutical composition for preventing or treating anticancer drug-resistant cancer comprising an MRTF A inhibitor.
- Another embodiment of the present invention relates to a method for preventing or treating anticancer drug-resistant cancer, comprising administering an effective amount of an MRTF A inhibitor to a subject in need of administration.
- the method comprising: contacting a candidate material with a biological sample comprising Myocardin-related transcription factor A (MRTF A) or a cell expressing the same; And it relates to a screening method of a drug for overcoming anticancer drug resistance or therapeutic drug or anticancer drug sensitivity enhancement comprising the step of measuring the activity or expression level of the MRTF A protein or a gene encoding the same after the treatment of the candidate substance.
- MRTF A Myocardin-related transcription factor A
- the present inventors obtained human cells from the American Type Culture Collection (ATCC) and the Korean Cell Line Bank (KCRB).
- ATCC American Type Culture Collection
- KCRB Korean Cell Line Bank
- Cell lines MKN1, HS746T, human-derived gastric cancer cell lines, SNU601, YCC7 and NCIN87 cells having characteristics of derived gastric cancer stem cells were obtained.
- Each of the cell lines was cultured by changing the culture medium and culture conditions according to the ATCC or KCRB guide.
- the MKN1, SNU601, and NCIN87 cell lines were cultured in RPMI1640 medium containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin, while the HS746T and YCC7 cell lines were cultured in 10 % FBS, 2 mM L-glutamine, 100 U ml penicillin, and cultured in DMEM medium containing 100 ⁇ g / ml streptomycin. All cell lines were cultured at 37 °C, 5% CO 2 environment, and mycoplasma contamination test was performed.
- FBS fetal bovine serum
- 2 mM L-glutamine 100 U/ml penicillin
- streptomycin 100 fetal bovine serum
- Example 1 Confirmation of the therapeutic effect of cancer cells and cancer stem cells upon treatment of CCG-232601
- the cell line cultured in the above preparation example was aliquoted in a well plate at a concentration of 1 x 10 4 cells per well, and cultured overnight at 37 °C, 5% CO 2 environment. Thereafter, cisplatin (CDDP), an anticancer drug, and the MRTF A inhibitor, CCG-232601, were administered at different concentrations during the treatment of gastric cancer patients, respectively, in gastric cancer stem-like cells HS746T and MKN1 cell lines and gastric cancer cells YCC7 and NCIN87 cell lines. It is shown in Figure 1 by comparing the number of cells after 48 hours of treatment.
- OCR oxygen consumption
- ECAR extracellular matrix oxidation
- Transwell Transwell invasion assay with or without CCG-232601 treatment was performed.
- the invasion ability was measured using a 6.5 mm transwell with an 8.0 ⁇ m-pore polycarbonate membrane insert (Corning) after coating with Matrigel (Corning) diluted to 0.67 ⁇ g/ ⁇ l in serum-free medium.
- 2 ⁇ 10 4 cells per well were suspended in 200 ⁇ l of serum-free medium with vehicle or 10 ⁇ g/ml CCG-232601, and 1000 ⁇ l of culture medium containing 10% FBS was added to the lower chamber.
- the metastasized cells were stained with 0.2% crystal violet and observed under a light microscope.
- the average number of cells penetrating the membrane was calculated by ImageJ (NIH) in three randomly selected high-power fields and two independent experiments, and the results are shown in FIG. 3 .
- the compound according to the present invention can inhibit cancer cell invasion and cancer metastasis very effectively by inhibiting MRTFA/SRF of cancer cells.
- Fig. 3 shows the results of measuring drug sensitivity to cisplatin (CDDP) treatment, which appears in gastric cancer cell lines, SNU601 and NCIN87 cell lines, and HS746T and MKN1 cell lines, which have similar characteristics to gastric cancer stem cells.
- CDDP drug sensitivity to cisplatin
- CCG-232601 survival and Growth inhibitory effect was confirmed using a cell viability assay kit (Cell Counting Kit-8; CCK-8).
- CCG-232601, CCG-203971 or CCG-222740 5 ⁇ g/ml was firstly administered to the HS746T cell line, and when 24 hours had elapsed, cisplatin (CDDP) 5 ⁇ M was secondarily administered. Over time, the results were confirmed with a cell viability assay kit (CCK-8 assay).
- the MRTF A inhibitor according to the present invention has an effect of improving the reactivity of anticancer agents, particularly platinum-based anticancer agents, and thus can impart a synergistic effect to growth inhibition of cancer stem cells, as well as platinum-based anticancer agents. It can be seen that anticancer drug resistance can also be overcome.
- composition according to the present invention can overcome resistance to anticancer drugs and at the same time enhance anticancer drug sensitivity, and further effectively prevent, improve or treat anticancer drug-resistant cancer.
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Abstract
Description
Claims (23)
- MRTF A(Myocardin-related transcription factor A) 억제제를 포함하는 항암제 내성 치료용 약학적 조성물.
- 제 1항에 있어서,상기 항암제는 시스플라틴, 카보플라틴 및 옥살리플라틴으로 이루어진 군에서 선택된 1 종 이상인, 조성물.
- 제 1항에 있어서,상기 조성물은 추가로 다른 항암제를 더 포함하는, 조성물.
- 제 5항에 있어서,상기 항암제는 시스플라틴, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 베바시주맙, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1 종 이상인, 조성물.
- 제 6항에 있어서,상기 항암제는 백금 계열의 항암제로서, 시스플라틴, 카보플라틴 및 옥살리플라틴으로 이루어진 군으로부터 선택되는 적어도 하나인, 조성물.
- 제 7항에 있어서,상기 항암제는 시스플라틴인, 조성물.
- MRTF A(Myocardin-related transcription factor A) 억제제를 포함하는 항암제 감수성 증진용 약학적 조성물.
- 제 9항에 있어서,상기 항암제는 시스플라틴, 카보플라틴 및 옥살리플라틴으로 이루어진 군에서 선택된 1 종 이상인, 조성물.
- 제 9항에 있어서,상기 조성물은 추가로 다른 항암제를 더 포함하는 것인, 조성물.
- 제 13항에 있어서,상기 항암제는 시스플라틴, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 베바시주맙, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1 종 이상인, 조성물.
- 제 14항에 있어서,상기 항암제는 백금 계열의 항암제로서, 시스플라틴, 카보플라틴 및 옥살리플라틴으로 이루어진 군으로부터 선택되는 적어도 하나인, 조성물.
- 제 15항에 있어서,상기 항암제는 시스플라틴인, 조성물.
- MRTF A(Myocardin-related transcription factor A) 억제제를 포함하는 항암제 내성암의 예방 또는 치료용 약학적 조성물.
- 제 17항에 있어서,상기 조성물은 추가로 다른 항암제를 더 포함하는 것인, 조성물.
- 제 20항에 있어서,상기 항암제는 시스플라틴, 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 베바시주맙, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 1 종 이상인, 조성물.
- 제 17항에 있어서,상기 암은 위암, 유방암, 대장암, 폐암, 간암, 식도암, 췌장암, 담낭암, 신장암, 방광암, 전립선암, 고환암, 결장암, 자궁경부암, 자궁내막암, 융모암, 피부암, 난소암, 갑상선암, 뇌암, 혈액암, 두경부암, 악성흑색종 및 림프종으로 이루어진 군으로부터 선택되는 적어도 하나인 것인, 조성물.
- 다음의 단계를 포함하는 항암제 내성 치료용 조성물의 스크리닝 방법:a) MRTF A(Myocardin-related transcription factor A) 또는 이를 발현하는 세포를 포함하는 생물학적 시료와 후보물질을 접촉시키는 단계; 및b) 상기 MRTF A 단백질 또는 이를 코딩하는 유전자의 활성 또는 발현 수준을 측정하는 단계, 상기에서 측정된 활성 또는 발현 수준이 감소한 경우 상기 후보물질을 항암제 내성 치료용 조성물로 판정한다.
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