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WO2025067453A1 - Combinaison pharmaceutique comprenant un inhibiteur de kras, composition la comprenant, et son utilisation - Google Patents

Combinaison pharmaceutique comprenant un inhibiteur de kras, composition la comprenant, et son utilisation Download PDF

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Publication number
WO2025067453A1
WO2025067453A1 PCT/CN2024/121824 CN2024121824W WO2025067453A1 WO 2025067453 A1 WO2025067453 A1 WO 2025067453A1 CN 2024121824 W CN2024121824 W CN 2024121824W WO 2025067453 A1 WO2025067453 A1 WO 2025067453A1
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pharmaceutical composition
dosage form
substance
pharmaceutical
cancer
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Chinese (zh)
Inventor
傅新元
马中南
吴沙沙
俞强
刘新宇
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Generos Biopharma Ltd China
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Generos Biopharma Ltd China
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a drug combination containing a KRAS inhibitor, a composition containing the drug combination and application thereof.
  • Pancreatic cancer is the fourth leading cause of cancer death worldwide, with a five-year survival rate of less than 9%.
  • the incidence of pancreatic cancer ranks among the top 10 of all malignant tumors, and the incidence is gradually increasing. In general, the incidence of pancreatic cancer is higher in developed countries than in developing countries. Pancreatic cancer is a highly malignant digestive system tumor, and China is expected to have more than 120,000 new cases/deaths in 2022. In 2040, the growth rate of new cases and deaths from pancreatic cancer will reach 88.8%. The mortality rate ranks sixth. Surgery is still the only possible way to cure pancreatic cancer. Although there are currently no targeted and immunotherapeutic drugs for pancreatic cancer, clinical research on related monoclonal antibodies has been ongoing.
  • KRAS gene point mutations are closely related to pancreatic cancer. Studies have reported that the mutation rate of KRAS in pancreatic ductal carcinoma is about 90%, and its codon 12 is a hotspot for mutation, so the detection of this point mutation has important clinical value for the diagnosis, prognosis and monitoring of pancreatic cancer.
  • Colorectal cancer is one of the most common malignant tumors of the digestive tract, and its incidence and mortality rate rank third and fourth among urban malignant tumors, respectively. Compared with other advanced malignant tumors of the digestive tract, the 5-year survival rate of colorectal cancer patients has been significantly improved due to the popularization of early diagnosis and detection, the discovery of new molecular targets, and the use of corresponding targeted drugs.
  • the launch of the targeted drug cetuximab has made great progress in the treatment of colorectal cancer, but about 40% of colorectal cancer patients have mutations in the KRAS gene, and these patients cannot benefit from cetuximab treatment, so the treatment of colorectal cancer still faces huge challenges. Exploring new mechanisms and treatment combinations for colorectal cancer is still an important issue that needs to be urgently addressed in the clinic of colorectal cancer.
  • Non-small cell lung cancer has the highest mortality rate among all cancers in my country.
  • NSCLC Non-small cell lung cancer
  • NSCLC non-small cell lung cancer
  • chemotherapy is still the main treatment for lung cancer.
  • chemotherapy-based treatments in the past decade have not made a breakthrough in the efficacy of non-small cell lung cancer.
  • KRAS gene mutation is considered to be a poor prognostic factor for patients with non-small cell lung cancer.
  • most studies believe that patients with KRAS G12C mutations in lung adenocarcinoma have significantly worse overall survival than patients with non-mutated KRAS.
  • Non-small cell lung cancer with KRAS gene mutations has gone through stages such as chemotherapy, chemotherapy combined with anti-angiogenic drugs, chemotherapy combined with immunotherapy, and targeted drug therapy.
  • Amgen's KRAS small molecule inhibitor has been approved for non-small cell lung cancer, but it is not good for treating resistant and insensitive patients.
  • KRAS mutant solid tumors such as combination therapy targeting different pathways.
  • One possible approach is to use drug combinations as multi-target drugs. In the best case, this can produce additive efficiency, such as synergy, which may even reduce the undertreatment caused by a single drug when used alone.
  • Compound 1 It is a highly selective small molecule covalent inhibitor of the KRAS G12C mutation, forming an irreversible covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state to prevent downstream signaling without affecting wild-type KRAS.
  • the FDA has approved two similar products, AMG510 and MRTX849, and compound 1 has better KRAS inhibition ability.
  • Fedratinib is the second targeted drug approved by the US Food and Drug Administration for the treatment of myelofibrosis after Ruxolitinib.
  • Fedratinib is an oral JAK2 selective inhibitor with a strong inhibitory effect on JAK2. Its inhibitory effects on JAK1, TYK2 and JAK3 are about 30, 100 and 300 times weaker than JAK2, respectively. In addition, it still has the ability to inhibit FLT3 and RET activity. (Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor in treatment of a murine model of JAK2 V617F-induced polycythemia vera[J]. Cancer Cell, 2008, 13(4):311-320).
  • Fidatinib is a new JAK inhibitor that has shown a certain effect on myelofibrosis symptoms in clinical studies by inhibiting the (JAK/STAT) pathway. Because it has the ability to inhibit the activity of FLT3, RET, and JAK2, it has a better effect on inhibiting tumor cell proliferation and has an inhibitory effect on some tumor cells.
  • fidatinib and KRAS inhibitors have not yet been used in combination to treat solid tumors, especially KRAS mutant solid tumors.
  • the technical problem solved by the present invention is to provide a drug combination containing a KRAS inhibitor, a composition containing the same and its application.
  • the KRAS inhibitor of the present invention can be used in combination with a JAK inhibitor.
  • the drug combination of the KRAS inhibitor and the JAK inhibitor of the present invention exerts a synergistic effect, can be used to treat KRAS mutant tumors, and has good application prospects.
  • the present invention provides a pharmaceutical composition A, comprising: a substance X and a substance Y;
  • the substance X is a JAK inhibitor or a pharmaceutically acceptable salt thereof;
  • the JAK inhibitor is Fidatinib Ruxolitinib and baricitinib One or more of;
  • the substance Y is a compound containing a fragment as shown in Formula I or a pharmaceutically acceptable salt thereof;
  • n1 0, 1, 2, 3 or 4;
  • R1 is H or halogen
  • Each R 2 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with one or more CN;
  • Ring A is a benzene ring or a 6-8 membered heterocyclic ring; the heterocyclic ring in the 6-8 membered heterocyclic ring is a saturated or unsaturated monocyclic ring, the heteroatom is N and/or O, and the number of the heteroatom is 1, 2 or 3;
  • Ring B is an unsaturated 6-8 membered heterocyclic ring; in the unsaturated 6-8 membered heterocyclic ring, the heteroatom is N and/or O, and the number of the heteroatom is 1, 2 or 3.
  • n3 is 0, 1 or 2;
  • n4 is 0 or 1
  • n5 is 0, 1, 2, 3 or 4;
  • Each R 3 is independently C 1 -C 6 alkyl or -NR a R b ; preferably Methyl or isopropyl;
  • Each R 4 is independently halogen, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens; preferably fluorine, chlorine or -CF 3 ;
  • Each R 5 is independently -OH, halogen, C 1 -C 6 alkyl, -NR a R b or C 1 -C 6 alkyl substituted by one or more halogens; preferably -OH, -NH 2 , -CF 3 , fluorine, chlorine or methyl;
  • Ra is H or C1 - C6 alkyl
  • R b is H or C 1 -C 6 alkyl.
  • the compound containing the fragment as shown in Formula I is Preferably More preferably
  • the JAK inhibitor in the drug combination A, is fidatinib.
  • the drug combination A has a synergistic effect.
  • the molar ratio of the substance X to the substance Y may be (0.1-500):1, preferably (5-500):1, and more preferably 5:1, 23:1, 25:1, 125:1, 200:1 or 250:1.
  • the active ingredients of the pharmaceutical combination A consist of substance X as described above and substance Y as described above.
  • the active ingredients of the drug combination A are fidatinib and composition.
  • the active ingredients of the drug combination A are fidatinib and composition.
  • the active ingredients of the drug combination A are fidatinib and composition.
  • the present invention provides a pharmaceutical composition B, which comprises: substance X, substance Y and pharmaceutical excipients;
  • the substance X is a JAK inhibitor or a pharmaceutically acceptable salt thereof;
  • the JAK inhibitor is Fidatinib Ruxolitinib and baricitinib In One or more;
  • the substance Y is a compound containing a fragment as shown in Formula I or a pharmaceutically acceptable salt thereof;
  • n1, R 1 , R 2 , ring A and ring B are as described above.
  • the JAK inhibitor is fidatinib.
  • the pharmaceutical composition B has a synergistic effect.
  • the content of the substance X is preferably 50-600 mg; more preferably 100-400 mg; for example 200 mg.
  • the molar ratio of the substance X to the substance Y may be (0.1-500):1, preferably (5-500):1, and more preferably 5:1, 23:1, 25:1, 125:1, 200:1 or 250:1.
  • the active ingredient of the pharmaceutical composition B consists of substance X as described above and substance Y as described above.
  • the active ingredients of the pharmaceutical composition B are fidatinib and composition.
  • the active ingredients of the pharmaceutical composition B are composed of fidatinib and composition.
  • the active ingredients of the pharmaceutical composition B are composed of fidatinib and composition.
  • the pharmaceutical composition B may be a separate pharmaceutical composition.
  • the pharmaceutical composition B can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids.
  • gastrointestinal dosage forms such as oral dosage forms
  • parenteral dosage forms such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms
  • capsules preferably capsules, tablets, pills, granules, powders or oral liquids.
  • the pharmaceutical composition B is preferably presented in an oral dosage form.
  • composition C comprising:
  • the first pharmaceutical composition C-1 comprises a substance X and a pharmaceutical excipient, wherein the substance X is a JAK inhibitor or a pharmaceutically acceptable salt thereof; the JAK inhibitor is Fidatinib Ruxolitinib and baricitinib One or more of; and,
  • the second pharmaceutical composition C-2 comprises a substance Y and a pharmaceutical excipient, wherein the substance Y is a compound containing a fragment as shown in Formula I or a pharmaceutically acceptable salt thereof;
  • n1, R 1 , R 2 , ring A and ring B are as described above.
  • the JAK inhibitor is fidatinib.
  • the pharmaceutical composition C has a synergistic effect.
  • the first pharmaceutical composition C-1 may be a separate pharmaceutical composition; and the second pharmaceutical composition C-2 may be a separate pharmaceutical composition.
  • the content of the substance X is preferably 50-600 mg; more preferably 100-400 mg; for example 200 mg.
  • the molar ratio of the substance X to the substance Y may be (0.1-500):1, preferably (5-500):1, and more preferably 5:1, 23:1, 25:1, 125:1, 200:1 or 250:1.
  • the pharmaceutical composition C preferably consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2.
  • the first pharmaceutical composition C-1 is preferably composed of the substance X as described above and a pharmaceutical excipient, more preferably composed of Fidatinib and a pharmaceutical excipient.
  • the second pharmaceutical composition C-2 is preferably composed of the substance Y as described above and a pharmaceutical excipient, and more preferably is composed of any of the following compounds and a pharmaceutical excipient: For example, and pharmaceutical excipients.
  • the first pharmaceutical composition C-1 can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory dosage forms, mucosal dosage forms).
  • gastrointestinal dosage forms such as oral dosage forms
  • parenteral dosage forms such as injection dosage forms, respiratory dosage forms, mucosal dosage forms.
  • the invention relates to a dosage form for oral administration or a dosage form for oral administration), preferably a capsule, a tablet, a pill, a granule, a powder or an oral liquid; for example, it is presented in the form of an oral dosage form.
  • the second pharmaceutical composition C-2 can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids; for example, presented in the form of oral dosage forms.
  • gastrointestinal dosage forms such as oral dosage forms
  • parenteral dosage forms such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms
  • the first pharmaceutical composition C-1 is in an oral dosage form
  • the second pharmaceutical composition C-2 is in an oral dosage form
  • the present invention provides a combination medicine kit D, which comprises:
  • a first container comprising the first pharmaceutical composition C-1 as described above;
  • the second container comprises the second pharmaceutical composition C-2 as described above.
  • the present invention also provides the use of the above-mentioned drug combination A, drug composition B or drug composition C in the preparation of a drug for a proliferative disease;
  • the proliferative disease is preferably cancer or a tumor;
  • the cancer or tumor is more preferably one or more of intestinal cancer, pancreatic cancer, non-small cell lung cancer, solid tumor, melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, small cell lung cancer, sarcoma, intestinal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell tumor, Wilms' tumor and hepatocellular carcinoma; for example, intestinal cancer, pancreatic cancer, non-small cell lung cancer or
  • the present invention also provides the use of the above-mentioned drug combination A, drug composition B or drug composition C in the preparation of a drug for a proliferative disease carrying a KRAS mutation;
  • the proliferative disease is preferably a proliferative disease carrying a KRAS mutant; the KRAS mutant in the proliferative disease with a KRAS mutant is more preferably one or more of A146T, Q61L, Q61K, G12D, G12C, G13D, G12V, G12R and G13C; for example, G12C.
  • the proliferative disease carrying a KRAS mutation may be KRAS G12C mutant colorectal cancer, KRAS G12C mutant pancreatic cancer, KRAS G12C mutant ovarian cancer, KRAS G12C mutant non-small cell lung cancer or KRAS G12C mutant solid tumor.
  • the present invention also provides a method for preventing and/or treating a proliferative disease, comprising administering a therapeutically effective amount of the above-described drug combination A, drug composition B or drug composition C to a subject (e.g., a human) or patient in need thereof; the proliferative disease is as described above.
  • the present invention also provides a method for preventing and/or treating a proliferative disease carrying a KRAS mutant, comprising administering a therapeutically effective amount of the above-described drug combination A, drug composition B or drug composition C to a subject (e.g., a human) or a patient in need thereof; the proliferative disease carrying a KRAS mutant is as described above.
  • the substance X and substance Y may be administered simultaneously or separately.
  • spontaneous administration means, for example, that substance X and substance Y are contained in separate pharmaceutical compositions and administered simultaneously; or, "comprising substance X
  • the "separate pharmaceutical composition comprising substance Y” is administered simultaneously with the "separate pharmaceutical composition comprising substance Y".
  • the "separate administration” is, for example, "a separate pharmaceutical composition containing substance X" and "a separate pharmaceutical composition containing substance Y" are separately administered at different times, for example: one of "a separate pharmaceutical composition containing substance X” and "a separate pharmaceutical composition containing substance Y" is administered first, and the other is administered subsequently.
  • the separate administration may be close in time or far in time.
  • the administration regimens (including administration routes, administration doses, administration intervals, etc.) of the substance X and substance Y may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.
  • the substance X can be administered gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), respiratory tract, or topically (e.g., mucosa or skin); preferably, administered gastrointestinal tract, such as orally.
  • the substance Y can be administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), respiratory tract, or topically (e.g., mucosa or skin); preferably, it can be administered via the gastrointestinal tract, such as orally.
  • the substance X is preferably administered orally; and, the substance Y is preferably administered orally.
  • the total daily dosage of the substance X can be administered according to clinical needs; the total daily dosage range is preferably 50-1000 mg; for example, 200 mg, 400 mg or 600 mg.
  • the administration frequency of the substance X can be adjusted according to clinical needs; preferably once a day or twice a day; for example, once a day.
  • the total daily dosage of the substance X is preferably in the range of 50-1000 mg, such as 200 mg, 400 mg or 600 mg; the administration frequency is preferably once a day or twice a day, such as once a day.
  • the substance X is orally administered according to the above-mentioned total dosage and frequency.
  • the substance X is administered orally at a dose of 200 mg to 1000 mg, once a day or twice a day.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and the preparation of prescriptions; it is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • the term “content” refers to the mass of a certain component contained in a specific substance.
  • the content of the substance X in the pharmaceutical composition B refers to the mass of the component X contained in the pharmaceutical composition B;
  • the content of the substance X in the first pharmaceutical composition C-1 refers to the mass of the component X contained in the first pharmaceutical composition C-1.
  • treat refers to any of the following: (1) ameliorating one or more biological manifestations of a disease; (2) interfering with the one or more points in a biological cascade; (3) slowing the progression of one or more biological manifestations of a disease.
  • therapeutically effective amount refers to the amount of a compound administered to a subject that is sufficient to effectively treat a disease.
  • the therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the subject, etc., but can be adjusted by those skilled in the art as appropriate.
  • subject refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
  • the structural fragment is connected to the rest of the molecule through this bond.
  • It refers to pyridyl.
  • one or more means 1, 2, 3, 4 or 5, for example 1, 2 or 3.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1 -C 6 ).
  • Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • heterocycle refers to a cyclic, saturated or unsaturated group having a specified number of ring atoms (e.g., 5-12 members, 6-8 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S, such as N and/or O).
  • ring atoms e.g., 5-12 members, 6-8 members
  • heteroatoms e.g., 1, 2 or 3
  • a specified heteroatom type one or more of N, O and S, such as N and/or O.
  • heterocycles include, but are not limited to:
  • the reagents and raw materials used in the present invention are commercially available.
  • KRAS inhibitors can be used in combination with JAK inhibitors, have a good inhibitory effect on the proliferation of cancer cells (especially the proliferation of KRAS mutant cancer cells), can be used to treat KRAS mutant tumors including pancreatic cancer, non-small cell lung cancer, intestinal cancer and solid tumors, and have good application prospects. Furthermore, the combination of KRAS inhibitors and JAK inhibitors is significantly better than the use of JAK inhibitors and KRAS inhibitors alone, and exerts a synergistic effect.
  • the synergy described in the present invention refers to the effect of two therapeutic agents (e.g., Fidatinib and Compound 1), which produces an effect (e.g., slowing down the progression of symptoms of a proliferative disease, particularly cancer, or its syndrome) that is greater than the effect of simply adding each drug to be administered by itself.
  • the inhibitory effect of the combination of the KRAS inhibitor and the JAK inhibitor of the present invention in the anti-proliferation experiment of KRAS G12C mutant tumor cells meets one or more of the following: that is, within the same observation window (72 hours), relative to the 100% growth capacity of the cell sample treated with the solvent DMSO, the combined treatment method can significantly reduce the cell proliferation capacity as follows:
  • the combination of KRAS inhibitor and JAK inhibitor of the present invention overcomes the problem of KRAS drug resistance in people receiving KRAS G12C drug treatment, and further solves the problem of drug resistance of KRAS mutant tumors including pancreatic cancer, non-small cell lung cancer, colorectal cancer and solid tumors (Zhao, Y., et al., Diverse alterations associated with resistance to KRAS (G12C) inhibition. Nature, 2021. 599 (7886): p. 679-683.).
  • Figure 1 shows the results of the in vitro synergistic inhibition of the proliferation of different cancer cells with KRAS G12C mutation by compound 1 and fidatinib, wherein A is the combined inhibitory effect of compound 1 (250 nM) and different concentrations of fidatinib (0.039 ⁇ M-1.25 ⁇ M) on the proliferation of MIA-PACA2 cells; B is the combined inhibitory effect of compound 1 (10 nM) and different concentrations of fidatinib (0.63 ⁇ M-2.5 ⁇ M) on the proliferation of MIA-PACA2 cells resistant to compound 1; C is the combined inhibitory effect of compound 1 (10 nM) and different concentrations of fidatinib (0.63 ⁇ M-2.5 ⁇ M) on the proliferation of NCI-H358 cells; D is the combined inhibitory effect of different concentrations of compound 1 (12.5 nM-50 nM) and different concentrations of fidatinib (2.5 ⁇ M-10 ⁇ M) on the proliferation of MIA-PACA2
  • FIG2 shows the experimental results of the effect of the combination of Compound 1 and Fidatinib on the early apoptosis of MIA-PACA2 cells, Compound 1-resistant MIA-PACA2 cells, NCI-H358 cells and SW1463 cells.
  • FIG. 3 shows the results of clone formation experiments of MIA-PACA2 cells, MIA-PACA2 cells resistant to compound 1, NCI-H358 cells, and SW1463 cells.
  • FIGS 4 and 5 show the results of protein immunoblotting of MIA-PACA2 cells.
  • FIG6 shows the experimental results of the combination of Compound 1 and Fidatinib on the changes in tumor volume in a mouse model of human non-small cell lung cancer.
  • FIG7 shows the experimental results of the combination of Compound 1 and Fidatinib on the changes in body weight of mice in a human non-small cell lung cancer model.
  • FIG8 shows the experimental results of the combination of compound 1 and Fidatinib on the changes in tumor volume in a human pancreatic cancer mouse model.
  • FIG9 shows the experimental results of the combination of Compound 1 and Fidatinib on the changes in mouse body weight in a human pancreatic cancer model.
  • FIG10 shows the combined inhibitory effect of compound 1 (0.25 ⁇ M) and different concentrations of tofacitinib (0.04 ⁇ M-1.25 ⁇ M) on the proliferation of SW837 cells.
  • FIG11 shows the combined inhibitory effect of compound 1 (0.25 ⁇ M) and different concentrations of tofacitinib (0.04 ⁇ M-1.25 ⁇ M) on the proliferation of Calu-1 cells.
  • FIG12 shows the combined inhibitory effect of compound 1 (0.25 ⁇ M) and different concentrations of tofacitinib (0.04 ⁇ M-1.25 ⁇ M) on the proliferation of MIA-PACA2 cells.
  • FIG13 shows the combined inhibitory effect of compound 1 (0.25 ⁇ M) and different concentrations of tofacitinib (0.04 ⁇ M-1.25 ⁇ M) on the proliferation of NCI-H358 cells.
  • MIA-PACA2 cells MIA-PACA2 cells, NCI-H358, SW1463 cells, and DMEM/F12 culture medium were purchased from Wuhan Pronocell Biotechnology Co., Ltd.
  • MIA-PACA2_R/Compound 1-0.5 ⁇ M refers to a MIA-PACA2 cell line resistant to Compound 1.
  • the cell line was obtained by long-term (3 weeks) culture with low concentration (0.5 ⁇ M) Compound 1, the culture conditions were DMEM medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, cultured in a humidified incubator at 37 degrees and 5% carbon dioxide concentration, drug treatment, and the culture medium was changed twice a week.
  • CCK8 reagent, DMEM, RPMI 1640, fetal bovine serum (FBS), 0.25% EDTA trypsin, PBS, and penicillin-streptomycin (P/S) were purchased from Beijing Quanshijin Biotechnology Co., Ltd.; dimethyl sulfoxide (DMSO) was purchased from Shanghai Solebow Biotechnology Co., Ltd.; Fedratinib was purchased from Haoyuan Biotechnology (HY-10409); Compound-1 was commissioned to Wuhan WuXi AppTec Co., Ltd. for synthesis.
  • DMEM:FBS:P/S was prepared at a ratio of 89:10:1.
  • MIA-PACA2 cells MIA-PACA2 cells, NCI-H358 cells, SW1463 cells, and DMEM/F12 culture medium were purchased from Wuhan Pronocell Biotechnology Co., Ltd. Limited company;
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • PBS penicillin-streptomycin
  • DMSO dimethyl sulfoxide
  • V/PI apoptosis kit was purchased from Suzhou Youyi Landi Biotechnology Co., Ltd.
  • ACEA NovoCyte series flow cytometer was purchased from Agilent Technologies Co., Ltd.;
  • DMEM:FBS:P/S was prepared at a ratio of 89:10:1.
  • MIA-PACA2 cells MIA-PACA2 cells, NCI-H358, SW1463 cells, and DMEM/F12 culture medium were purchased from Wuhan Pronocell Biotechnology Co., Ltd.
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • PBS penicillin-streptomycin
  • DMSO dimethyl sulfoxide
  • crystal violet staining solution was purchased from Shanghai Biyuntian Biotechnology Co., Ltd.
  • DMEM:FBS:P/S was prepared at a ratio of 89:10:1.
  • MIA-PACA2 cells were purchased from Wuhan Pronocell Biotechnology Co., Ltd.
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • P/S penicillin-streptomycin
  • 6 ⁇ loading buffer 6 ⁇ loading buffer
  • Protein Marker (10-180 kDa) were purchased from Beijing Quanshijin Biotechnology Co., Ltd.
  • dimethyl sulfoxide (DMSO) was purchased from Shanghai Solebao Biotechnology Co., Ltd.
  • pErk1/2 (T202/Y204) antibody, pSTAT3 (Y705) antibody, and pJAK2 (Y1007/1008) antibody were purchased from Cell Signaling Technology (CST);
  • GAPDH antibody, ammonium persulfate (APS), glycine, Tris, SDS, and 1% dapoxetine were purchased from Shanghai Shenggong Biotechnology Co., Ltd.
  • 10 ⁇ SDS-PAGE electrophoresis buffer Dissolve 30.2 g Tris powder, 144 g glycine, and 10 g SDS in 1 mL of deionized water. Dilute to 1 ⁇ electrophoresis buffer in deionized water before use.
  • 1 ⁇ TBST buffer Take 50 mL of 20 ⁇ TBS, dilute it in 1 L of deionized water, and add 1 mL of Tween-20;
  • Drug dilution Take 10 mM compound 1 and Fedratinib stock solutions and dilute them to the required concentration with DMSO;
  • DMEM:FBS:P/S was prepared at a ratio of 89:10:1.
  • the selected female Balb/c Nude mice were 5 weeks old and purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.
  • NCI-H358 non-small cell lung cancer cells (Human Non-small Cell Lung Cancer Cells) were isolated from the tumor tissue of a patient before chemotherapy in 1981. This cell line carries the KRAS p.G12C heterozygous mutation.
  • NCI-H358 cells were cultured in RPMI-1640 (15% FBS + 1% Penicillin-Streptomycin Solution) at 5% CO 2 and 37°C. After cell digestion and counting, the cell suspension was mixed with Matrigel (Corning HC 354248) in a 1:1 ratio and kept in an ice bath throughout the process. 1*10E7 cells were inoculated subcutaneously in the right armpit of mice. After 11 days of inoculation, the tumor volume reached an average of 200 mm 3 and group dosing began.
  • Drug administration and data analysis Drug administration was stopped on the 21st day of inoculation, and endpoint statistical analysis was performed on the 24th day to compare the changes in mouse tumor volume. The results are shown in Figures 6 and 7.
  • the tumor in the control group showed a growth trend, with an average growth of 276.5%.
  • the tumor in the GEC5 group remained stable without obvious tumor shrinkage effect.
  • the FED7 group had no obvious tumor shrinkage effect and could not maintain tumor stability.
  • Comb7 significantly shrank tumors, with an average tumor shrinkage rate of 33.9%.
  • the GEC5 monotherapy group had a significant inhibitory effect on tumor growth, with a tumor growth inhibition rate of 50.58%, and the tumor volume remained stable and non-progressive, with no reduction effect;
  • the Fedratinib monotherapy group had no significant inhibitory effect on the tumor, with a tumor growth inhibition rate of 28.96%.
  • the combination group Comb7 had a significant inhibitory effect on tumor proliferation, with a tumor growth inhibition rate of 73.57%, and had a significantly better tumor shrinkage effect than the GEC5 and Fedratinib monotherapy groups.
  • the selected female Balb/c Nude mice were 5 weeks old and purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.
  • MIA-PACA2 cells were purchased from Wuhan Pronocell Biotechnology Co., Ltd. and cultured in DMEM (10% FBS + 1% Penicillin-Streptomycin Solution) at 5% CO 2 and 37°C. After cell digestion and counting, the cells were kept in an ice bath throughout the process. 5*10E6/cells were inoculated subcutaneously in the right armpit of mice. After 30 days of inoculation, the tumor volume reached an average of about 200 mm 3 and grouping and dosing began.
  • DMEM % FBS + 1% Penicillin-Streptomycin Solution
  • Comb7 had a significant tumor growth inhibitory effect, and its tumor inhibition ability was better than that of GEC5 and FED7 groups.
  • Drug administration was stopped on the 10th day after drug treatment, endpoint statistics were performed on the 11th day, and the tumor volume changes of mice before and after drug treatment were analyzed and compared on the 12th day. The results are shown in Figures 8 and 9.
  • the tumor in the control group showed a significant growth trend, with an average growth rate of 162.7%.
  • the tumor volume in the GEC5 group remained stable without growth.
  • the FED7 group had poor tumor inhibition ability and the tumor showed a growth trend.
  • the Comb7 combined treatment group had significant tumor shrinkage, with an average tumor shrinkage rate of 78.0%.
  • MIA-PACA2 cells MIA-PACA2 cells, NCI-H358, Calu-1, SW837 cells, and DMEM/F12 culture medium were purchased from Wuhan Pronocell Biotechnology Co., Ltd.
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • PBS penicillin-streptomycin
  • DMSO dimethyl sulfoxide
  • MB4155 Tofacitinib
  • HY-K0302 was purchased from MCE.
  • DMEM:FBS:P/S was prepared at a ratio of 89:10:1.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne une combinaison pharmaceutique comprenant un inhibiteur de KRAS, une composition la comprenant, et son utilisation. La combinaison pharmaceutique A comprend une substance X et une substance Y, la substance X étant un inhibiteur de JAK ou un sel pharmaceutiquement acceptable de celui-ci ; l'inhibiteur de JAK est un ou plusieurs éléments parmi fedratinib, ruxolitinib et baricitinib ; la substance Y est un composé comprenant un fragment tel que représenté dans la formule I ou un sel pharmaceutiquement acceptable de celui-ci. L'utilisation combinée de l'inhibiteur de KRAS et de l'inhibiteur de JAK a un effet synergique, et la perspective d'application est bonne.
PCT/CN2024/121824 2023-09-27 2024-09-27 Combinaison pharmaceutique comprenant un inhibiteur de kras, composition la comprenant, et son utilisation Pending WO2025067453A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (3)

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US20160166571A1 (en) * 2014-09-18 2016-06-16 Araxes Pharma Llc Combination therapies for treatment of cancer
WO2019141250A1 (fr) * 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c
WO2022052895A1 (fr) * 2020-09-11 2022-03-17 南京明德新药研发有限公司 Forme cristalline d'un composé à substitution azétidine

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Publication number Priority date Publication date Assignee Title
US20160166571A1 (en) * 2014-09-18 2016-06-16 Araxes Pharma Llc Combination therapies for treatment of cancer
WO2019141250A1 (fr) * 2018-01-19 2019-07-25 南京明德新药研发股份有限公司 Dérivé de pyridone-pyrimidine agissant en tant qu'inhibiteur de mutéine krasg12c
WO2022052895A1 (fr) * 2020-09-11 2022-03-17 南京明德新药研发有限公司 Forme cristalline d'un composé à substitution azétidine

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ENTRIALGO-CADIERNO RODRIGO, CUETO-UREÑA CRISTINA, WELCH CONNOR, FELIU IKER, MACAYA IRATI, VERA LAURA, MORALES XABIER, MICHELINA SA: "The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer", MOLECULAR CANCER, BIOMED CENTRAL, LONDON, GB, vol. 22, no. 1, 1 May 2023 (2023-05-01), GB , pages 86 - 23, XP093297743, ISSN: 1476-4598, DOI: 10.1186/s12943-023-01788-w *
KITAZAWA MASATO, MIYAGAWA YUSUKE, KOYAMA MAKOTO, NAKAMURA SATOSHI, HONDO NAO, MIYAZAKI SATORU, MURANAKA FUTOSHI, TOKUMARU SHIGEO, : "Drug sensitivity profile of minor KRAS mutations in colorectal cancer using mix culture assay: The effect of AMG‑510, a novel KRAS G12C selective inhibitor, on colon cancer cells is markedly enhanced by the combined inhibition of MEK and BCL‑XL", MOLECULAR AND CLINICAL ONCOLOGY, SPANDIDOS PUBLICATIONS, GR, vol. 15, no. 1, GR , XP055961549, ISSN: 2049-9450, DOI: 10.3892/mco.2021.2310 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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