WO2021098679A1 - Fak抑制剂在制备用于治疗nras突变的肿瘤的药物中的用途 - Google Patents

Fak抑制剂在制备用于治疗nras突变的肿瘤的药物中的用途 Download PDF

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WO2021098679A1
WO2021098679A1 PCT/CN2020/129350 CN2020129350W WO2021098679A1 WO 2021098679 A1 WO2021098679 A1 WO 2021098679A1 CN 2020129350 W CN2020129350 W CN 2020129350W WO 2021098679 A1 WO2021098679 A1 WO 2021098679A1
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cancer
tumor
fak inhibitor
therapeutic agent
paclitaxel
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French (fr)
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王在琪
张江伟
江君
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Inxmed Nanjing Co Ltd
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Inxmed Nanjing Co Ltd
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Priority to AU2020388848A priority Critical patent/AU2020388848A1/en
Priority to US17/777,769 priority patent/US20230145356A1/en
Priority to CA3158585A priority patent/CA3158585A1/en
Priority to KR1020227020144A priority patent/KR20220101677A/ko
Priority to BR112022009571A priority patent/BR112022009571A2/pt
Priority to EP20890277.5A priority patent/EP4062914A4/en
Priority to MX2022005994A priority patent/MX2022005994A/es
Priority to CN202080078892.0A priority patent/CN114667144A/zh
Application filed by Inxmed Nanjing Co Ltd filed Critical Inxmed Nanjing Co Ltd
Priority to JP2022529446A priority patent/JP7681910B2/ja
Priority to PE2022000810A priority patent/PE20221259A1/es
Publication of WO2021098679A1 publication Critical patent/WO2021098679A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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 invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to the use of a FAK inhibitor in the preparation of a medicament for the treatment of tumors with NRAS mutations.
  • FAK also known as protein tyrosine kinase 2 (PTK2)
  • PTK2 protein tyrosine kinase 2
  • FAK plays an important role in mediating integrin and growth factor signals to regulate tumor cell invasion, proliferation and survival.
  • FAK is widely expressed and evolutionarily conserved.
  • Studies in the past two decades have shown that FAK is overexpressed in a variety of solid tumors, and the expression level is negatively correlated with tumor prognosis.
  • Recent studies have also shown that FAK plays an important role in regulating the tumor microenvironment, suggesting that FAK plays an important role in the adaptive drug resistance of immunotherapy and anti-tumor therapy. Both in vitro and in vivo preclinical studies have shown that blocking FAK has anti-tumor effects.
  • the inhibitory activity of FAK inhibitors on tumors varies greatly.
  • BI853520 is a FAK inhibitor. BI853520 exhibits different anti-tumor activities in CDX (human tumor cell line transplanted mice) models of 37 different tumor types, and its TGI (tumor growth inhibition) span ranges from 0-107 % Varies. How to use it more targeted to inhibit tumor growth is an urgent technical problem in this field.
  • the present invention provides a use of a FAK inhibitor in the preparation of a medicament for treating tumors with NRAS mutations.
  • the FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718 or a pharmaceutically acceptable salt thereof.
  • the FAK inhibitor is BI853520 or a pharmaceutically acceptable salt thereof, especially BI853520 tartrate.
  • the BI 853520 has the following structure:
  • the drug is used in combination with an effective amount of a second therapeutic agent.
  • the drug is used in combination with radiotherapy or cell therapy.
  • the tumor is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, cholangiocarcinoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myeloid Leukemia, chronic myeloid leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, liposarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, Angiosarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell Cancer, nasopharyngeal cancer, oropharyngeal
  • the second therapeutic agent is selected from one or more of chemotherapeutic agents, targeted therapeutic agents and immunotherapeutic agents.
  • the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, ifosfamide, glyphosyl mustard, deoxyfluoroguanosine, poly Cifluguanidine, fluorouracil, mercaptopurine, mercaptothioprine, mercaptoguanine, fluguanosine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, ufludine, calcin Pecitabine, Acitabine, Cetepa, Actinomycin D, Adriamycin, Liposome Adriamycin, Daunorubicin, Epirubicin, Mitomycin, Pingyangmycin, Pirubicin Picin, valrubicin, idarubicin, irinotecan, triapexine, camptothecin, hydroxycamptothecin, topotecan, vin
  • the second therapeutic agent is selected from the group consisting of decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, doxorubicin, liposomal doxorubicin, paclitaxel, docetaxel, trime Tinib, bimetinib, cobitinib, devaluzumab, atezolizumab, sintilizumab, teriprizumab, carrelizumab, tislelizumab , Nivolumab, Pembrolizumab.
  • the second therapeutic agent docetaxel, liposomal adriamycin, cobitinib, pembrolizumab, and decitabine;
  • the second therapeutic agent is cobitinib.
  • the present invention also provides a method for treating tumors with NRAS mutations, which comprises administering an effective amount of FAK inhibitor to the individual.
  • the FAK inhibitor is BI853520 or defactinib, GSK2256098, PF-00562271, VS-4718 or a pharmaceutically acceptable salt thereof, preferably BI853520 or a pharmaceutically acceptable salt thereof, especially BI853520 tartrate.
  • it further comprises administering to the individual an effective amount of a second therapeutic agent.
  • it further includes radiotherapy or cell therapy.
  • the tumor is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, cholangiocarcinoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myeloid Leukemia, chronic myeloid leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, liposarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, Angiosarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell Cancer, nasopharyngeal cancer, oropharyngeal
  • the second therapeutic agent is selected from one or more of chemotherapeutic agents, targeted therapeutic agents and immunotherapeutic agents.
  • the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, ifosfamide, glyphosyl mustard, deoxyfluoroguanosine, poly Cifluguanidine, fluorouracil, mercaptopurine, mercaptothioprine, mercaptoguanine, fluguanosine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, ufludine, calcin Pecitabine, Acitabine, Cetepa, Actinomycin D, Adriamycin, Liposome Adriamycin, Daunorubicin, Epirubicin, Mitomycin, Pingyangmycin, Pirubicin Picin, valrubicin, idarubicin, irinotecan, triapexine, camptothecin, hydroxycamptothecin, topotecan, vin
  • the second therapeutic agent is selected from the group consisting of decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, doxorubicin, liposomal doxorubicin, paclitaxel, docetaxel, trime Tinib, bimetinib, cobitinib, devaluzumab, atezolizumab, sintilizumab, teriprizumab, carrelizumab, tislelizumab , Nivolumab, Pembrolizumab.
  • the second therapeutic agent docetaxel, liposomal adriamycin, cobitinib, pembrolizumab, and decitabine;
  • the second therapeutic agent is cobitinib.
  • the second therapeutic agent is administered synchronously, alternately or sequentially.
  • the FAK inhibitor and radiotherapy or cell therapy are performed synchronously, alternately or sequentially.
  • the present invention provides a FAK inhibitor for treating tumors with NRAS mutations.
  • the FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718 or a pharmaceutically acceptable salt thereof, preferably BI853520 or a pharmaceutically acceptable salt thereof, especially BI853520 tartrate.
  • it is further used in combination with an effective amount of a second therapeutic agent.
  • the tumor is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, cholangiocarcinoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myeloid Leukemia, chronic myeloid leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, liposarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, Angiosarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell Cancer, nasopharyngeal cancer, oropharyngeal
  • the second therapeutic agent is selected from one or more of chemotherapeutic agents, targeted therapeutic agents and immunotherapeutic agents.
  • the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, ifosfamide, glyphosyl mustard, deoxyfluoroguanosine, poly Cifluguanidine, fluorouracil, mercaptopurine, mercaptothioprine, mercaptoguanine, fluguanosine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, ufludine, calcin Pecitabine, Acitabine, Cetepa, Actinomycin D, Adriamycin, Liposome Adriamycin, Daunorubicin, Epirubicin, Mitomycin, Pingyangmycin, Pirubicin Picin, valrubicin, idarubicin, irinotecan, triapexine, camptothecin, hydroxycamptothecin, topotecan, vin
  • the second therapeutic agent is selected from the group consisting of decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, doxorubicin, liposomal doxorubicin, paclitaxel, docetaxel, trime Tinib, bimetinib, cobitinib, devaluzumab, atezolizumab, sintilizumab, teriprizumab, carrelizumab, tislelizumab , Nivolumab, Pembrolizumab.
  • the second therapeutic agent docetaxel, liposomal adriamycin, cobitinib, pembrolizumab, and decitabine;
  • the second therapeutic agent is cobitinib.
  • FAK inhibitor refers to an effective inhibitor of FAK, which may be suitable for mammals, especially humans.
  • NRAS refers to an oncogene, a member of the RAS oncogene family, which also includes two other genes: KRAS and HRAS. These genes play an important role in cell division, cell differentiation and apoptosis.
  • NRAS mutation means that when a pathogenic mutation occurs in the NRAS gene, the N-Ras protein encoded by it will be in a state of continuous activation, leading to uncontrolled cell proliferation and the formation of tumors.
  • treatment refers to the administration of one or more drug substances (especially the FAK inhibitors described herein, especially BI853520 or its pharmaceutically acceptable The salt) is used to cure, alleviate, alleviate, change, cure, improve, improve or affect the disease or the symptoms of the disease.
  • the disease is tumor or cancer.
  • the disease is a cancer or tumor in which NRAS mutations occur.
  • tumor refers to the abnormal pathological changes in which the cells of the local tissue lose their normal regulation of their growth at the gene level under the action of various tumor-causing factors, resulting in abnormal clonal proliferation.
  • examples include, but are not limited to: Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, cholangiocarcinoma, myelodysplastic syndrome, acute lymphocytic leukemia, acute myeloid Leukemia, chronic myeloid leukemia, thyroid cancer, glioma, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, breast cancer, liposarcoma, fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, Angiosarcoma, neuroblastoma, renal cell carcinoma, head and neck cancer, gastric cancer, esophageal
  • the term "individual” as used herein refers to mammals and non-mammals. Mammal refers to any member of the mammalian class, which includes but is not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cows, horses, sheep, goats, and pigs; Domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and so on. Examples of non-mammals include but are not limited to birds and the like.
  • the term "individual” does not limit a specific age or gender. In some embodiments, the individual is a human.
  • pharmaceutically acceptable refers to non-toxic, biologically tolerable, and suitable for administration to an individual.
  • pharmaceutically acceptable salt refers to a non-toxic, biologically tolerable acid addition salt of BI853520 suitable for administration to an individual, including but not limited to: the acid formed by BI853520 and inorganic acid Addition salts, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by BI853520 with organic acids, such as methyl Acid salt, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxy Ethyl sulfonate, benzoate, salicylate, stearate, and salt formed with alkane dicarboxylic acid of the formula HOOC-(CH 2 ) n -COOH (wherein n is 0-4), etc.
  • Addition salts such as hydrochlor
  • a pharmaceutically acceptable acid addition salt can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid in accordance with the conventional operation for preparing an acid addition salt from a basic compound.
  • Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation.
  • the term "effective amount” as used herein refers to an amount generally sufficient to produce a beneficial effect on an individual.
  • Conventional methods such as modeling, dose escalation studies, or clinical trials
  • conventional influencing factors such as the method of administration, the pharmacokinetics of the compound, the severity and course of the disease, the individual's medical history, the individual's health, the individual The degree of response to the drug, etc.
  • second therapeutic agent refers to one or more drug substances used to prevent and/or treat diseases.
  • the second therapeutic agent is selected from one or more of chemotherapeutic agents, targeted therapeutic agents and immunotherapeutic agents.
  • the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, ifosfamide, glycosyl mustard, deoxyfluoguanosine , Doxyfluguanidine, Fluorouracil, Mercaptopurine, Mercaptopurine, Mercaptoguanine, Fluguanosine, Tegafur, Gemcitabine, Decitabine, Carmofur, Hydroxyurea, Methotrexate, Ufludine , Capecitabine, amcitabine, cetepa, actinomycin D, doxorubicin, liposomal doxorubicin, daunorubicin, epirubicin, miomycin,
  • the second therapeutic agent is selected from the group consisting of decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, doxorubicin, liposomal doxorubicin, paclitaxel, docetaxel, and Trimex Tinib, bimetinib, cobitinib, devaluzumab, atezolizumab, sintilizumab, teriprizumab, carrelizumab, tislelizumab , Nivolumab, Pembrolizumab.
  • the second therapeutic agent docetaxel, liposomal adriamycin, cobitinib, pembrolizumab, decitabine; optionally, the second therapeutic agent is a test Bitinib.
  • the drug substance selected from the second therapeutic agent will be slightly different due to different translations, but they refer to a drug substance, for example: Cobimetinib (also known as Cobimetinib) .
  • inhibitor refers to a reduction in the baseline activity of a biological activity or process.
  • Figure 1 shows the effect of IL-3 on the anti-proliferative effect of BI 853520 in the Ba/F3-NRAS G12D cell line.
  • IC 50 increase more than 4 times.
  • Figure 3 shows the HT-1080 tumor growth kinetics.
  • the tumor volume of treated BI 853520 6mg / kg median of 322mm 3 BI 853520 treatment to 12.5mg / kg of tumor volume
  • the median was 149 mm 3
  • the median tumor volume treated with 25 mg/kg BI 853520 was 15 mm 3
  • the median tumor volume treated with 50 mg/kg BI 853520 was 322 mm 3 .
  • Figure 4 shows the KYSE-270 tumor growth kinetics, which shows that the median tumor volume of the control group increased from 179 mm 3 to 1032 mm 3 , compared with the control group, the tumor volume treated with 50 mg/kg BI 853520 per day
  • the median decreased from 175mm 3 to 126mm 3 , once a week treatment with 10mg/kg paclitaxel had no effect on tumor growth, the median tumor volume increased from 190mm 3 to 1033mm 3 , once a day with 50mg/kg BI 853520 and weekly a combination therapy 10mg / kg paclitaxel, a significant delay of tumor growth, tumor volume median dropped from 173mm 3 to 87mm 3.
  • Figure 5 shows the change in body weight. It showed that the median weight of animals in the control group decreased by 10.3%. Compared with the control group, the median weight of animals treated with 50 mg/kg BI 853520 per day increased by 2.8%, and paclitaxel was used once a week at 10 mg/kg. The median weight of the treated animals decreased by 9.7%, and the combined treatment of 50 mg/kg BI 853520 once a day and 10 mg/kg paclitaxel once a week increased the median weight of the animals by 3.5%.
  • Figure 6 shows GAK tumor growth kinetics. It shows that in the GAK model, compared with the control group, daily BI 853520 treatment delayed tumor growth.
  • Figure 7 shows HMVII tumor growth kinetics. It shows that in the HMVII model, compared with the control group, daily BI 853520 treatment delayed tumor growth.
  • Example I The correlation between BI853520's anti-tumor effect and NRAS
  • the Ba/F3 cell line was obtained from ATCC in 2009, and according to Zhang X, Ren R. Bcr-abl, efficiently induce a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor for novel model: A Chronic myelogenous leukemia. Blood., 1998, 92: 3829-40.
  • the growth factor-dependent BA/F3 cells were cultured in RPMI 1640 containing 10% FBS, and supplemented with 15% WEHI-3 conditioned medium or recombinant IL-3 (Roche) as the source of IL-3, the final concentration was 1ng/ ml.
  • BI853520 Synthesized according to the method in patent WO2010058032.
  • NRAS G12D transfected Ba/F3 (Ba/F3-N) or KRAS G12D transfected Ba/F3 (Ba/F3-N) cells were seeded to 96 cells at a density of 5000 cells per well.
  • BI853520 was diluted 3-fold with RPMI 1640 at 9 points, and added according to the volume of each well, starting at 10 ⁇ mol/L, reaching a 3-fold concentration gradient (final solvent concentration ⁇ 1/1000).
  • Ba/F3 is a cell line derived from murine bone marrow that depends on IL-3 for survival and proliferation. It has been successfully used in the high-throughput analysis of kinase drug discovery.
  • NRAS G12D oncogenic NRAS
  • Figure 1 and Table 1 show the anti-proliferative effect of BI853520 on the Ba/F3-NRAS G12D cell line, with an IC 50 value of 3.4 ⁇ M. The IC 50 increased by more than 4 times after IL-3 was added, indicating that the inhibitory effect was related to NRAS.
  • Table 1 The effect of adding IL-3 on the anti-proliferative effect of BI853520 in Ba/F3-NRAS G12D cell line
  • Example 2 The effect of BI853520 in a mouse model of human fibrosarcoma (cell line HT-1080)
  • BI 853520 50mg/kg, 25mg/kg, 12.5mg/kg, 6mg/kg,
  • Evaluation of treatment outcome is based on the absolute volume of a single tumor
  • Tolerance is evaluated based on changes in body weight.
  • BI853520 Synthesized according to the method in patent WO2010058032. The dry powder was suspended in 0.5% hydroxyethyl cellulose to reach the concentration required for each experiment. The pH of this formulation is 3.5.
  • HT-1080 cells carrying NRAS, CDKN2A and IDH1 gene mutations are from ATCC (CRL-121). The cells were grown in T175 tissue culture flasks with DMEM+Glutamax supplemented with 10% heat-inactivated fetal bovine serum as the medium. The cells were cultured in humidified air at 37°C and 5% CO 2.
  • mice Athymic female BomTac, approximately 6-week-old NMRI-Foxn1 nu mice were purchased from Taconic, Denmark. After arriving in the animal room, the mice adapt to the new environment for at least 3 days before being used in the experiment. These animals were kept under standard conditions (temperature 21.5 ⁇ 1.5°C and 55 ⁇ 10% humidity), with 5 groups per group. Standardize diet and provide autoclaved tap water ad libitum. Datamars T-IS 8010 FDX-B transponders implanted subcutaneously in the neck area and LabMax II fixed readers were used to identify each mouse. The cage card shows the study number, animal identification number, compound and dose level, route of administration, and the animal's dosing schedule throughout the experiment.
  • HT-1080 cells were collected, centrifuged, washed by trypsin digestion and resuspended in ice-cold PBS + 1 x 10 8 cells / ml medium. Then 100 ⁇ l of cell suspension containing 1 x 10 7 cells was injected subcutaneously into the right flanks of nude mice (1 site per mouse). When the tumor formed and reached a diameter of 5-8 mm (7 days after cell injection), the mice were randomly assigned to the treatment group and the blank control group.
  • BI853520 is suspended in 0.5% hydroxyethyl cellulose and administered intragastrically via a gavage needle every day, with a dosage of 10 mL/Kg.
  • the mice were checked daily for abnormalities, and the body weight was measured daily. The animals were sacrificed at the end of the study (approximately two weeks after the start of the treatment); during the study, for ethical reasons, animals with tumor necrosis or tumors larger than 2000 mm 3 would be sacrificed early.
  • the tumor volume and body weight parameters were statistically evaluated.
  • the absolute value of the tumor volume and the percentage change in body weight (refer to the initial weight on day 1) were used.
  • a non-parametric method was used to calculate the number of observations, median, minimum and maximum.
  • the median tumor volume of each treatment group T and the median tumor volume of the control group C are used to calculate the TGI from day 1 to day d:
  • TGI 100x[(C d -C 1 )-(T d -T 1 )]/(C d -C 1 )
  • C 1 , T 1 the median tumor volume of the control group and the treatment group on the first day of the experiment
  • C d , C d The median tumor volume of the control group and the treatment group at the end of the experiment on the 13th day
  • a unilateral decrement wilcoxon test was used to compare each dose of the test compound with the control group.
  • the reduction in tumor volume was used as a therapeutic effect, and the weight loss was used as a side effect.
  • the P value of tumor volume (efficacy parameter) has been compared and adjusted many times, while the P value of body weight (tolerability parameter) has not been adjusted to avoid ignoring possible side effects.
  • P-value (after adjustment) less than 0.05 is considered to show a statistically significant difference between the groups, when 0.05 ⁇ p-value ⁇ 0.10, the difference is regarded as an indicative difference.
  • the software package SAS version 9.2 SAS Institute Inc., North Carolina, North Carolina, USA
  • Proc StatXact version 8.0 were used for statistical evaluation.
  • BI 853520 showed statistically significant anti-tumor activity at all dose levels, and regression was observed in all treatment groups; at the highest dose level, tumor volume reduction was observed in all animals. In previous studies, the highest dose taken per day was 100 mg/kg, with no limiting toxicity. Therefore, a significant therapeutic effect was obtained at a dose (6 mg/kg) that was at least 16 times lower than the MTD.
  • Example 3 BI 853520 subcutaneous xenograft mouse model derived from the human esophageal cancer cell line KYSE-270 in NMRI nude mice Anti-tumor activity
  • Model subcutaneously xenotransplanted human esophageal cancer cell line KYSE-270 in NMRI nude mice.
  • Test compound BI853520: synthesized according to the method in patent WO2010058032.
  • KYSE-270 is an esophageal cancer cell line (Public Health England, catalog number: 94072021). At 37°C, the cells were cultured in T175 tissue culture flasks containing 5% CO 2. The medium used was RPMI 1640+HAM F12 (1:1) supplemented with 2% FCS and 2mM Glutamax. Passaged at a ratio of 1:2 three times a week.
  • mice Female mice (BomTac:NMRI-Foxn1 nu ) between 8 and 10 weeks old purchased from Taconic, Denmark. After arriving in the animal room, allow the mice to adapt for at least 5 days before being used in the experiment. These animals are kept under standard conditions (temperature 21.5+1.5°C, humidity 55+10%), in groups of 7 to 10. Provide standard diet and autoclaved tap water for free consumption. Subcutaneous microchips implanted under isoflurane anesthesia were used to identify each mouse. Show study number, animal identification number, compound and dose level, route of administration, and the animal's dosing schedule throughout the experiment are retained on the animal.
  • BI 853520 Suspend BI 853520 in 0.5% hydroxyethylcellulose, and administer intragastrically via a gavage needle every day, the dosage is 10mL/Kg body weight.
  • Paclitaxel was dissolved in saline (0.9% NaCl) and administered intravenously with a volume of 10 ml/kg body weight.
  • the suspension of BI853520 can be used for up to 7 days.
  • the paclitaxel solution is stored at a temperature of 6°C for a maximum of 14 days.
  • the tumor volume and body weight on the 13th day were statistically evaluated. Animal number 1 (blank control group) was excluded from the statistical evaluation because of weight loss and must be euthanized as soon as possible (day 9). In the statistical analysis, the measured tumor volume was used as the target variable. The number of animals in each group, the median, minimum and maximum tumor volume were calculated. In order to quickly understand the possible treatment effects, the median tumor volume of each treatment group T and the median tumor volume of the control group C are used to calculate the TGI:
  • TGI 100x[(C d -C 1 )-(T d -T 1 )]/(C d -C 1 )
  • C 1 , T 1 the median tumor volume of the control group and the treatment group on the first day of the experiment
  • C d , C d The median tumor volume of the control group and the treatment group at the end of the experiment on the 13th day
  • the Wilcoxon test was used for comparison.
  • body weight the percentage change from the initial body weight on day 1 was used as the target variable for the statistical analysis. Calculate the number of animals in each group, the median, minimum and maximum weight changes.
  • the p-value of the efficacy parameter was compared and adjusted several times.
  • the p-value of the tolerance parameter remains unchanged, so as not to ignore possible side effects.
  • the adjusted p value less than 0.05 is considered to show a statistically significant difference between the groups, and when 0.05 ⁇ p value ⁇ 0.10, the difference is considered indicative.
  • the statistical evaluation was carried out using SAS 9.4 version software package (SAS Institute Inc., Cary NC, USA).
  • Table 4 TGI, tumor shrinkage and weight change in each group (day 13)
  • Example 4 BI 853520's effect on tumor growth of HMVII and GAK CDX models (melanoma models with NRAS mutations) Growth inhibition
  • Test compound BI853520, which was synthesized according to the method in patent WO2010058032.
  • BI853520 is formulated with 0.5% hydroxyethyl cellulose (Ashland).
  • the melanoma cell line GAK was purchased from JCRB cell bank, and HMVII cells were purchased from Sigma. GAK originates from the inguinal lymph nodes of patients with vaginal melanoma, while HMVII originates from primary vaginal melanoma.
  • GAK and HMVII cells were cultured in tissue culture flasks containing 5% CO 2 with the medium of Ham's F12 containing 10% heat-killed FBS and Ham's F10 containing 15% FBS. All media were supplemented with 100U/mL penicillin, 100mg/mL streptomycin and 2mM GlutaMAX. All cell culture reagents were purchased from GIBCO.
  • HMVII and GAK cell lines carry the NRAS mutation at position Q61.
  • HMVII of NRAS Q61K and GAK of NRAS Q61L carry the NRAS mutation at position Q61.
  • mice Female balb/c nude mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) about 4 weeks old. After arriving in the animal room, allow the mice to adapt to the new environment for at least 2 weeks before being used in the experiment. The animals are kept under standard conditions (temperature 21.5 ⁇ 1.5°C and 55 ⁇ 10% humidity). Provide standard diet and autoclaved tap water freely. All animal care and experimental procedures were performed in accordance with the animal care ethics guidelines approved by the Medical Ethics Committee of Beijing Cancer Hospital and Research Institute.
  • HMVII and GAK cells were collected by trypsinization, centrifuged, washed and resuspended in ice-cold PBS+5% FCS. Then 100 ⁇ l of a cell suspension containing 5 ⁇ 10 6 cells was injected subcutaneously into the right flanks of nude mice (1 site per mouse). When the tumor was sufficiently established and reached a median volume of about 400-600 mm 3 , the mice were randomly allocated to the treatment group and the blank control group.
  • BI 853520 is configured in 0.5% hydroxyethyl cellulose and administered intragastrically via a gavage needle every day, the dosage is 10 mL/Kg body weight.
  • the tumor volume was statistically evaluated at the end of the experiment. For tumor volume, use relative values.
  • TGI 100x[(C d -C 1 )-(T d -T 1 )]/(C d -C 1 )
  • C 1 , T 1 the average relative tumor volume of the control group and the treatment group on the first day of the experiment
  • C d , C d the average of the relative tumor volume between the control group and the treatment group at the end of the experiment on day d
  • Table 5 Average tumor volume, average TGI and P value based on relative tumor volume on day 14
  • BI853520 can inhibit tumor growth in CDX models of HMVII and GAK (two melanoma models with NRAS mutations).

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Abstract

一种FAK抑制剂在制备用于预防和/或治疗NRAS突变的肿瘤的药物中的用途。一种治疗发生NRAS突变的肿瘤的方法，其包括向个体施用有效量的FAK抑制剂。用于治疗NRAS突变的肿瘤的FAK抑制剂。所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐。

Description

FAK抑制剂在制备用于治疗NRAS突变的肿瘤的药物中的用途 技术领域
本发明属于药物化学领域。具体地，本发明涉及一种FAK抑制剂在制备用于治疗NRAS突变的肿瘤的药物中的用途。
背景技术
FAK，又称为蛋白酪氨酸激酶2(PTK2)，是一种非受体酪氨酸激酶，并且是粘着斑复合体的关键组分。FAK在介导整合素和生长因子信号以调节肿瘤细胞的侵袭、增殖和存活方面发挥着重要作用。FAK广泛表达并且进化保守。过去二十年的研究表明，FAK在多种实体瘤中过度表达，且表达水平与肿瘤预后呈负相关。最近的研究也表明，FAK在调节肿瘤微环境中扮演着重要角色，提示FAK在免疫治疗和抗肿瘤治疗的适应性耐药中发挥着重要的作用。体外和体内临床前研究均显示阻断FAK具有抗肿瘤作用。但是FAK抑制剂对肿瘤的抑制活性差异很大。
BI853520是一种FAK抑制剂，在37种不同瘤种的CDX(人源肿瘤细胞系移植小鼠)模型中，BI853520表现出不同的抗肿瘤活性，其TGI(肿瘤生长抑制)跨度从0-107％不等。如何更有针对性的使用它抑制肿瘤生长是本领域亟待解决的技术问题。
发明内容
一方面本发明提供了一种FAK抑制剂在制备用于治疗NRAS突变的肿瘤的药物中的用途。
可选的，所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐。
可选的，所述FAK抑制剂为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
所述BI 853520，其具有以下结构：
Figure PCTCN2020129350-appb-000001
可选的，所述药物和有效量的第二治疗剂联用。
可选的，所述药物和放疗或者细胞治疗联用。
可选的，所述肿瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
可选的，所述第二治疗剂选自化疗剂，靶向治疗剂和免疫治疗剂中的一种或几种。
可选的，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种。
可选的，所述第二治疗剂选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗。
可选的，所述第二治疗剂多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；
可选的，所述第二治疗剂为考比替尼。
另一方面，本发明还提供了一种治疗发生NRAS突变的肿瘤的方法，其包括向个体施用有效量的FAK抑制剂。
可选的，所述FAK抑制剂为BI853520或defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐，优选为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
可选的，其进一步包括向个体施用有效量的第二治疗剂。
可选的，其进一步包括放疗或者细胞治疗。
可选的，所述肿瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
可选的，所述第二治疗剂选自化疗剂，靶向治疗剂和免疫治疗剂中的一种或几种。
可选的，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕 他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种。
可选的，所述第二治疗剂选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗。
可选的，所述第二治疗剂多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；
可选的，所述第二治疗剂为考比替尼。
可选的，所述第二治疗剂同步，交替或序贯给药。
可选的，所述FAK抑制剂和放疗或细胞治疗同步、交替或序贯进行。
再一方面，本发明提供了一种用于治疗NRAS突变的肿瘤的FAK抑制剂。
可选的，所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐，优选为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
可选的，其进一步和有效量的第二治疗剂联用。
可选的，其进一步与放疗或者细胞治疗联用。
可选的，所述肿瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
可选的，所述第二治疗剂选自化疗剂，靶向治疗剂和免疫治疗剂中的一种或几种。
可选的，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉 醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种。
可选的，所述第二治疗剂选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗。
可选的，所述第二治疗剂多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；
可选的，所述第二治疗剂为考比替尼。
定义
本申请中所用的下列术语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。
本文所述的术语“FAK抑制剂”是指FAK的有效抑制剂，可适于哺乳动物，特别是人。
本文所述的术语“NRAS”是指是一种致癌基因，是RAS致癌基因家族的一员，其中还包括另外两个基因：KRAS和HRAS。这些基因在细胞分裂、细胞分化和细胞凋亡中有着重要的作用。
本文所述的术语“NRAS突变”是指当NRAS基因发生致病性突变，其所编码的N-Ras蛋白将处于持续激活的状态，导致细胞增殖失控，进而形成肿瘤。
本文所用的术语“治疗”是指给患有疾病或者具有所述疾病的症状的个体施用一种或多种药物物质(特别是本文所述的FAK抑制剂，尤其是BI853520或其药学上可接受的盐)，用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。在一些实施方案中，所述疾病 是肿瘤或者癌症。在进一步的实施方案中，所述疾病是发生NRAS突变的癌症或肿瘤。
本文所用的术语“肿瘤”是指机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，从而导致其克隆型异常增生而形成的异常病变。实施例包括，但不限于：霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
本文所用的术语“个体”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，如黑猩猩及其它猿类和猴类物种；农场动物，如牛、马、绵羊、山羊和猪；家畜，如兔、狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠；等等。非哺乳动物的例子包括但不限于鸟等。术语“个体”并不限定特定的年龄或性别。在一些实施方案中，个体是人。
本文所用的术语“药学上可接受的”指的是无毒的、生物学上可耐受的，适合给个体施用的。
本文所用的术语“药学上可接受的盐”指的是无毒的、生物学上可耐受的适合给个体施用的BI853520的酸加成盐，包括但不限于：BI853520与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及BI853520与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH 2) n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。在一些实施方案中，所述盐为酒石酸盐。
此外，药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
本文所用的术语“有效量”是指通常足以对个体产生有益效果的量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、个体的病史、个体的健康状况、个体对药物的响应程度等)来确定本发明的化合物的有效量。
本文所用的术语“第二治疗剂”指的是一种或多种药物物质，用于预防和/或治疗疾病。在一些 实施方案中，所述第二治疗剂选自化疗剂，靶向治疗剂和免疫治疗剂中的一种或几种。在一些实施方案中，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种。可选的、所述第二治疗剂选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗。可选的、所述第二治疗剂多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；可选的、所述第二治疗剂为考比替尼。
此外，所述第二治疗剂选自的药物物质，因翻译不同，因此说法会略有差异，但它们指代的还是一种药物物质，例如：卡比替尼(Cobimetinib)别名考比替尼。
本文所用的术语“抑制”是指生物活动或过程的基线活性的降低。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
附图说明
附图1显示了IL-3对BI 853520在Ba/F3-NRAS G12D细胞系中抗增殖作用的影响。其显示对于BI853520，在NRAS G12D转染的Ba/F3细胞系中，添加IL-3后IC 50从3.4增至15μM，IC 50提高达到4倍以上。GraphPad Prism 6软件和学生t检验用于统计数据分析。统计学显著性差异阈值设置为P＝0.05。
附图2显示了体重的改变。其显示，空白对照组动物体重减轻了1.9％，以6mg/kg的BI 853520治疗的动物的体重中位数增加4.9％(与对照组相比，p＝0.9966)，以12.5mg/kg的BI 853520治疗的动物的体重中位数增加5.7％(与对照组相比，p＝0.9996)，以25mg/kg的BI 853520治疗的动物的体重中位数增加9.4％(与对照组相比，p＝1.0000)，以50mg/kg的BI 853520治疗的动物的体重中位数增加了8.3％(与对照组相比，p＝0.999)。
附图3显示了HT-1080肿瘤生长动力学。其显示在第13天，空白对照组的肿瘤体积中位数为823mm 3，以6mg/kg的BI 853520治疗的肿瘤体积中位数为322mm 3，以12.5mg/kg的BI 853520治疗的肿瘤体积中位数为149mm 3，以25mg/kg的BI 853520治疗的肿瘤体积中位数为15mm 3，以50mg/kg的BI 853520治疗的肿瘤体积中位数为322mm 3。
附图4显示了KYSE-270肿瘤生长动力学，其显示了对照组的肿瘤体积中位数从179mm 3增长到1032mm 3，与对照组相比，每天用50mg/kg BI 853520进行治疗的肿瘤体积中位数从175mm 3下降到126mm 3，每周一次用10mg/kg紫杉醇治疗对肿瘤生长没有影响，肿瘤体积中位数从190mm 3增长到1033mm 3，每天一次以50mg/kg BI 853520与每周一次10mg/kg紫杉醇的联合治疗，显着延迟了肿瘤的生长，肿瘤体积中位数从173mm 3下降到87mm 3。
附图5显示了体重的改变。其显示对照组动物的体重中位数下降了10.3％，与对照组相比，每天用50mg/kg BI 853520进行治疗的动物的体重中位数增加了2.8％，每周一次用10mg/kg紫杉醇治疗的动物的体重中位数减少了9.7％，每天一次以50mg/kg BI 853520与每周一次10mg/kg紫杉醇的联合治疗，动物的体重中位数增加了3.5％。
附图6显示了GAK肿瘤生长动力学。其显示在GAK模型中，与对照组相比，每天BI 853520进行治疗，延迟了肿瘤的生长。
附图7显示了HMVII肿瘤生长动力学。其显示在HMVII模型中，与对照组相比，每天BI 853520进行治疗，延迟了肿瘤的生长。
实施例
提供下面的实施例以进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明，而不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例中所用的缩写含义如下：
ATCC                   美国典型培养物保藏中心
CO 2                    二氧化碳
d                      天
FCS                    小牛血清
FBS                    胎牛血清
g                      克
kg                     千克
l                      升
mg                     毫克
ml                     毫升
μl                    微升
mM                     毫摩
mm 3                    立方毫米
GLP                    药物非临床研究质量管理规范
h                      小时
MCB                    原始细胞库
mean                   算术平均数
MTD                    最大耐受剂量
n                      样本量
PBS                    磷酸盐缓冲盐
RPMI 1640              RPMI 1640培养基
p.o.                   经口
qd                     每天
q7d                    每7天(每周一次)
s.c.                   皮下
SD                     标准差
TGI                      肿瘤生长抑制
WCB                      工作细胞库
V rel                     相对肿瘤体积(相对于第1天)
实施例I：BI853520抗肿瘤作用与NRAS的相关性
1.材料和方法：
1.1.DNA构建和逆转录病毒产生
参见Cuiffo B,Ren R.Palmitoylation of oncogenic NRAS is essential for leukemogenesis.Blood.,2010,115:3598–605和Parikh C,Subrahmanyam R,Ren R.Oncogenic NRAS,KRAS,and HRAS exhibit different leukemogenic potentials in mice.Cancer Res.,2007,67:7139–46所述方法产生表达NRAS-G12D、KRAS4A-G12D、KRAS4B-G12D和NRAS-G12D-C181S作为N-端GFP融合蛋白的逆转录病毒构建物。用Bosc23细胞制备逆转录病毒，并如Parikh C,Subrahmanyam R,Ren R.Oncogenic NRAS,KRAS,and HRAS exhibit different leukemogenic potentials in mice.Cancer Res.,2007,67:7139–46所述方法进行了滴度测定。
1.2.细胞培养和逆转录病毒转导
Ba/F3细胞系于2009年从ATCC获得，并按Zhang X,Ren R.Bcr-abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice:A novel model for chronic myelogenous leukemia.Blood.,1998,92:3829–40所述方法进行培养。将生长因子依赖性BA/F3细胞在包括10％FBS的RPMI 1640中培养，并补充15％WEHI-3条件培养基或重组IL-3(Roche)作为IL-3的来源，最终浓度为1ng/ml。如Parikh C,Subrahmanyam R,Ren R.Oncogenic NRAS,KRAS,and HRAS exhibit different leukemogenic potentials in mice.Cancer Res.,2007,67:7139–46和Fredericks J,Ren R.The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia.Front Med China.,2013,7:452–61所述方法用逆转录病毒转导BA/F3细胞。收到原始库存后，将细胞扩增并以低传代率(<3)冷冻。将冷冻的细胞解冻并用于本研究，所有实验程序的细胞传代限制为15次。所有细胞均定期检测，以确保支原体的自由和维持在正常状态。
1.3.材料
BI853520：按照专利WO2010058032中的方法合成。
1.4.抗增殖试验
在100μL培养基中，以每孔5000个细胞的密度将NRAS G12D转染的Ba/F3(Ba/F3-N)或KRAS G12D转染的Ba/F3(Ba/F3-N)细胞接种到96孔细胞培养丛板中。将BI853520用RPMI 1640在9个点进行3倍稀释稀释，并根据各孔的体积添加，以10μmol/L开始，达到3倍浓度梯度(最终溶剂浓度<1/1000)。以PD0325901为阳性对照。孵育48小时后，使用CellTiter Glo(Promega)测量细胞活力。使用Envision读板仪(PerkinElmer)检测发光。Z因子的计算方法如Zhang JH,Chung TDY,Oldenburg KR.A simple statistical parameter for use in evaluation and validation of high throughput screening assays.J Biomol Screen.,1999,4:67–73所述，以下分析仅使用Z因子>0.6的数据。使用GraphPad Prism 6软件(http://www.graphpad.com/scientific-software/prism/)，基于非线性适应度(曲线拟合)中的相对存活细胞百分比拟合剂量-响应曲线。内置软件分析“非线性回归(曲线拟合)”和方程式“对数(抑制剂)与响应变量斜率”用于数据分析和IC 50计算。
2.统计分析：
GraphPad Prism 6软件和学生t检验用于统计数据分析。统计学显著性差异阈值设置为P＝0.05。
3.结果：
Ba/F3是一种鼠骨髓来源的、依赖IL-3生存和增殖的细胞系，它已成功用于激酶药物发现的高通量分析。我们用致癌RAS测试了该系统，发现致癌NRAS(NRAS G12D)可以将Ba/F3细胞转化为独立于IL-3。图1和表1显示BI853520对Ba/F3-NRAS G12D细胞系的抗增殖作用，IC 50值为3.4μM。加入IL-3后IC 50的增加超过4倍，表明抑制作用与NRAS有关。
表1：是否添加IL-3对BI853520在Ba/F3-NRAS G12D细胞系中抗增殖作用的影响
Figure PCTCN2020129350-appb-000002
实施例2：BI853520在人纤维肉瘤小鼠模型中的作用(细胞系HT-1080)
1.材料和方法：
1.1.研究设计
当肿瘤的中位体积在70-130mm 3之间时开始治疗
空白对照组10只，治疗组每组7只
每日一次口服灌胃给药
空白对照：0.5％的羟乙基纤维素
BI 853520：50mg/kg，25mg/kg，12.5mg/kg，6mg/kg，
每周测量肿瘤体积3次，每日监测体重
治疗结果的评估是基于单个肿瘤的绝对体积
根据体重变化评估耐受性。
1.2.材料
BI853520：按照专利WO2010058032中的方法合成。将干粉悬浮在0.5％的羟乙基纤维素中，以达到每个实验所需的浓度。该配方的pH值为3.5。
HT-1080细胞：携带NRAS、CDKN2A和IDH1基因突变的HT-1080细胞来自ATCC(CRL-121)。细胞在T175组织培养瓶中生长，以添加10％热灭活胎牛血清的DMEM+Glutamax作为培养基。细胞在37℃和5％CO 2的加湿空气中培养。
鼠：无胸腺雌性BomTac，大约6周龄的NMRI-Foxn1 nu小鼠购自丹麦Taconic。在到达动物房后，老鼠在新的环境下适应至少3天，然后再用于实验。这些动物饲养在标准条件下(温度21.5±1.5℃和55±10％湿度)，每组5个一组。标准化饮食和随意提供高压灭菌的自来水。Datamars T-IS 8010 FDX-B皮下植入颈部区域的应答器和LabMax II固定式读取器被用来识别每只小鼠。笼卡上显示研究编号，动物识别号，化合物和剂量水平，给药途径以及在整个实验过程中动物的给药时间表都保留在动物身上。
1.3.随机建立肿瘤：
为建立皮下肿瘤，用胰酶消化法采集HT-1080细胞，离心、洗涤并悬浮在冰冷的PBS+1 x 10 8细胞/ml中。然后将含有1 x 10 7细胞的100μl细胞悬液皮下注射到裸鼠的右侧胁腹(每只小鼠1个位点)。当肿瘤形成并达到5-8mm直径(细胞注射后7天)时，将小鼠随机分配到治疗组和空白对照组。
1.4.给药：
BI853520悬浮于0.5％的羟乙基纤维素中，每日通过灌胃针胃内给药，给药量为10mL/Kg。
1.5.监测肿瘤生长和副作用：
每周用卡尺测量肿瘤直径三次(周一、周三和周五)。根据公式计算每个肿瘤的体积[以mm 3为单位]，“肿瘤体积＝长度x直径 2xπ/6”。为了监测治疗的副作用，每日检查小鼠的异常情况，并每日测定体重。动物在研究结束时处死(大约在治疗开始后两周)；在研究期间，出于伦理原因，肿瘤坏死或肿瘤大小超过2000mm 3的动物会提前被处死。
2.统计分析：
第13天实验结束时，对肿瘤体积和体重参数进行统计评估。肿瘤体积绝对值和体重的变化百分比(参考第1天的初始重量)被使用。采用了非参数方法，计算了观察次数、中位数、最小值和最大值。为了快速了解可能的治疗效果，每个治疗组T的肿瘤体积中位数和对照组C的肿瘤体积中位数被用于计算从第1天到第d天的TGI：
TGI＝100x[(C d-C 1)-(T d-T 1)]/(C d-C 1)
其中，C 1，T 1＝在实验开始第一天对照组和治疗组的肿瘤体积中位数
C d，C d＝第13天实验结束时对照组和治疗组肿瘤体积的中位数
采用单侧递减wilcoxon试验，将每个剂量的试验化合物与对照组进行比较，肿瘤体积减少作为治疗效果，体重减少作为副作用。根据Bonferroni-Holm对肿瘤体积(疗效参数)的P值进行了多次比较调整，而体重(耐受性参数)的P值未进行调整，以免忽略可能的副作用。显著性水平固定在α＝5％。p值(调整后)小于0.05的被认为显示出组间的统计学显著性差异，当0.05≤p值<0.10时，差异被视为指示性差异。使用软件包SAS版本9.2(SAS Institute Inc.，美国卡里北卡罗来纳州)和Proc StatXact版本8.0(Cytel软件公司，美国剑桥马萨诸塞州)进行统计评估。
3.结果：
3.1.在试验期间，空白对照组动物体重减轻了1.9％(图2，表2)，在第13天，它们的肿瘤体积中位数达到了823mm 3(图3，表3)。
3.2.每天一次以50mg/kg的BI 853520治疗，TGI为107％(p＝0.0002)，并且在所有动物中均观察到肿瘤缩小(图3，表3)。动物的体重中位数增加了8.3％(与对照组相比，p＝0.999)(图2，表2)。
3.3.每天一次以25mg/kg的BI 853520治疗，TGI为113％(p＝0.0002)，并且有6只动物的肿 瘤缩小(图3，表3)。动物的体重中位数增加9.4％(与对照组相比，p＝1.0000)(图2，表2)。
3.4.每天一次以12.5mg/kg的BI 853520治疗，TGI为94％(p＝0.0002),有2只动物的肿瘤缩小(图3，表3)。动物的体重中位数增加5.7％(与对照组相比，p＝0.9996)(图2，表2)。
3.5.每天一次以6mg/kg的BI 853520治疗，TGI为70％(p＝0.0004)，有1只动物的肿瘤缩小(图5，表3)。动物的体重中位数增加4.9％(与对照组相比，p＝0.9966)(图2，表2)。
表2：试验结束时体重中位数改变
剂量(mg/Kg) 给药时间表 体重中位数改变(％)
对照组 qd -1.9
50 qd +8.3
25 qd +9.4
12.5 qd +5.7
6 qd +4.7
表3：肿瘤中位体积
Figure PCTCN2020129350-appb-000003
4.结论：
在人HT-1080纤维肉瘤模型，BI 853520在所有剂量水平均显示出统计学显著性抗肿瘤活性，所有治疗组中均观察到消退；在最高剂量水平，所有的动物都观测到肿瘤体积缩小。在以前的研究中，每天服用的最高剂量为100mg/kg，没有限制性毒性。因此，以比MTD低至少16倍的剂量(6mg/kg)获得了显着的疗效。
实施例3：BI 853520在NMRI裸鼠的人食道癌细胞系KYSE-270衍生的皮下异种移植小鼠模 型中的抗肿瘤活性
1.材料与方法
1.1.模型：在NMRI裸鼠皮下异种移植人食道癌细胞系KYSE-270。
1.2.测试化合物：BI853520：按照专利WO2010058032中的方法合成。
1.3.细胞：KYSE-270是食道癌细胞系(英格兰公共卫生，目录号：94072021)。在37℃下，将细胞放置在含5％CO 2的T175组织培养瓶中培养。所用的培养基为补充有2％FCS和2mM Glutamax的RPMI 1640+HAM F12(1:1)。以1:2的比例每周传代三次。
1.4.老鼠：小鼠是从丹麦Taconic购买的8至10周大的雌鼠(BomTac：NMRI-Foxn1 nu)。到达动物房后，让小鼠至少适应5天，然后再用于实验。这些动物饲养在标准条件下(温度为21.5+1.5℃，湿度为55+10％)，以7到10个为一组。提供标准饮食和高压灭菌的自来水供自由采食。异氟烷麻醉下植入的皮下微芯片被用来识别每只小鼠。显示研究编号，动物识别编号，化合物和剂量水平，给药途径以及在整个实验过程中动物的给药时间表都保留在动物身上。
1.5.随机建立肿瘤：为了建立皮下肿瘤，通过离心收集KYSE-270细胞，洗涤并以5×10 7细胞/ml的浓度重悬于PBS+5％FCS中。将含有5×10 6个细胞的100μl细胞悬浮液皮下注射到小鼠的右侧胁腹(每只小鼠1个位点)。当肿瘤充分建立并且体积达到94至252mm 3时，将小鼠随机分配在治疗组和空白对照组(细胞注射后13天)。
1.6.给药：将BI 853520悬浮在0.5％的羟乙基纤维素中，每天通过灌胃针胃内给药，给药量为10mL/Kg体重。将紫杉醇(Paclitaxel)溶于盐水(0.9％NaCl)中，静脉内给药，体积为10ml/kg体重。BI853520的悬浮液最多使用7天。紫杉醇溶液在6℃的温度下保存，最多使用14天。
1.7.监测肿瘤的生长和副作用：每周用卡尺测量肿瘤直径三次。根据公式“肿瘤体积＝长度×直径 2×π/6”计算每个肿瘤的体积[mm 3]。为了监测治疗的副作用，每天检查小鼠的异常情况，且每周测量三次体重。出于伦理原因，对肿瘤直径超过1.5厘米，肿瘤溃烂或体重下降20％的动物进行安乐死。
2.统计分析：
对第13天的肿瘤体积和体重进行统计评估。动物编号1(空白对照组)从统计评估中排除了，因为体重减轻，必须尽早(第9天)安乐死。在统计分析中将测得的肿瘤体积作为目标变量。计算了每组的动物数量，肿瘤体积的中位数，最小值和最大值。为了快速了解可能的治疗效果，将每个治疗组T的肿瘤体积的中位数和对照组C的肿瘤体积中位数用于计算TGI：
TGI＝100x[(C d-C 1)-(T d-T 1)]/(C d-C 1)
其中，C 1，T 1＝在实验开始第一天对照组和治疗组的肿瘤体积中位数
C d，C d＝第13天实验结束时对照组和治疗组肿瘤体积的中位数
采用wilcoxon试验进行比较。对于体重，使用相对于第1天的初始体重的变化百分比用作统计 分析的目标变量。计算每组的动物数量，体重变化的中位数，最小值和最大值。
进行单方面测试以比较所有治疗组与对照组以观察
·肿瘤体积减少(抑制肿瘤生长，功效参数)
·减轻体重变化(体重减轻，耐受性参数)
在每个子主题内，根据Bonferroni-Holm对功效参数的p值进行多次比较调整。耐受性参数的p值保持不变，以免忽略可能的副作用。显着性水平固定为α＝5％。调整后的p值小于0.05被认为在各组之间显示出统计学上的显着差异，并且当0.05≤p值<0.10时，差异被认为是指示性的。统计评估是使用SAS 9.4版软件包(SAS Institute Inc.，美国Cary NC)进行的。
3.结果
肿瘤体积和体重：
直到第13天，对照组的肿瘤中位体积从179mm 3增长到1032mm 3(图4)。对照组动物的中位体重下降了10.3％(图5，表4)。第9天，一只动物由于体重严重下降，必须对其实施安乐死。
与对照组相比，每天用50mg/kg BI 853520进行治疗，显著延迟了肿瘤的生长(中位TGI＝106％，p＝0.0003)(图5，表4)。在第13天，7个中有6个肿瘤发生缩小(表4)。动物的中位体重增加了2.8％，与对照组无显着差异(p＝0.9999)(图5，表4)。
与对照相比，每周一次用10mg/kg紫杉醇治疗对肿瘤生长没有影响(中位TGI＝2％，p＝0.3788)(图4，表4)。在第13天，所有动物的肿瘤均没有发生缩小(表4)。动物的中位数体重减少了9.7％，与对照组无显着差异(p＝0.7320)(图5，表4)。
与对照组相比，每天一次以50mg/kg BI 853520加上每周一次10mg/kg紫杉醇的联合治疗，显着延迟了肿瘤的生长(中位TGI＝110％，p＝0.0003)(图4，表4)。在第13天，所有动物的肿瘤均发生缩小(表4)。动物的中位数体重增加了3.5％，与对照组无显着差异(p＝1.0000)(图5，表4)。
表4：每组TGI,肿瘤缩小和体重变化情况(第13天)
Figure PCTCN2020129350-appb-000004
4.结论
在皮下异种移植人食道癌细胞系KYSE-270的模型中，在使用50mg/kg BI 853520及与10mg/kg紫杉醇联用的治疗组中观察到统计学上显著的肿瘤生长抑制作用，且均耐受良好。
实施例4：BI 853520对HMVII和GAK CDX模型(带有NRAS突变的黑素瘤模型)的肿瘤生 长抑制作用
1.材料与方法
1.1.测试化合物：BI853520，按照专利WO2010058032中的方法合成BI853520。BI853520用0.5％的羟乙基纤维素(Ashland)配制。
1.2.细胞：黑色素瘤细胞系GAK购自JCRB细胞库，HMVII细胞购自Sigma。GAK起源于阴道黑素瘤患者的腹股沟淋巴结，而HMVII起源于原发性阴道黑素瘤。在37℃下，将GAK和HMVII细胞放置在含5％CO 2的组织培养瓶中培养，培养基分别为含有10％热灭FBS的Ham's F12，和含15％FBS的Ham's F10。所有培养基均补充有100U/mL青霉素，100mg/mL链霉素和2mM GlutaMAX。所有细胞培养试剂均购自GIBCO。
HMVII和GAK细胞系均在Q61位置携带NRAS突变。NRAS Q61K的HMVII和NRAS Q61L的GAK。
1.3.老鼠：约4周龄的雌性balb/c裸鼠(购自北京维通利华实验动物技术有限公司)。到达动物房后，让小鼠适应新环境至少2周，然后再用于实验。将动物饲养在标准条件下(温度21.5±1.5℃和55±10％湿度)。随意提供标准饮食和高压灭菌的自来水。所有动物护理和实验程序均按照北京肿瘤医院和研究所医学伦理委员会批准的动物护理伦理准则进行。
1.4.随机建立肿瘤：
为了建立皮下肿瘤，通过胰蛋白酶消化收集HMVII和GAK细胞，离心，洗涤并重悬于冰冷的PBS+5％FCS中。然后将100μl含有5×10 6个细胞的细胞悬浮液皮下注射到裸鼠的右侧胁腹(每只小鼠1个位点)。当肿瘤被充分地建立并达到约400-600mm 3的中值体积时，将小鼠随机分配在治疗组和空白对照组。
1.5.给药：将BI 853520配置在0.5％的羟乙基纤维素中，每天通过灌胃针胃内给药，给药量为10mL/Kg体重。
1.6.监测肿瘤的生长：
每周用卡尺测量肿瘤直径两次。根据公式“肿瘤体积＝长度×直径2×π/6”计算每个肿瘤的体积[mm 3]。在治疗开始后约两周，研究结束时处死动物。在研究过程中，出于伦理原因，将处死具有 坏死性肿瘤或肿瘤大小超过2000mm 3的动物。
2.统计分析：
在实验结束时对肿瘤体积进行统计学评估。对于肿瘤体积，使用相对值。
计算了观察次数，肿瘤体积的中位数，最小值和最大值。为了快速观察可能的治疗效果，计算了以下指标：
相对肿瘤体积：(T/C)
Figure PCTCN2020129350-appb-000005
从第一天到第d天的TGI：
TGI＝100x[(C d-C 1)-(T d-T 1)]/(C d-C 1)
其中，C 1，T 1＝在实验开始第一天对照组和治疗组的相对肿瘤体积平均数
C d，C d＝第d天实验结束时对照组和治疗组相对肿瘤体积的平均数
统计评估是使用Microsoft Excel中的学生t检验函数，使用两尾分布和两样本等方差类型。
显著性水平固定为α＝5％。认为(调整后的)p值小于0.05，表明治疗组之间存在显著差异，每当0.05≤p值<0.10时，该差异即为指示性。
3.结果
在GAK模型中，与对照组相比，每天BI 853520进行治疗，延迟了肿瘤的生长(中位TGI＝80％，p＝0.03)(图6，表5)。
在HMVII模型中，与对照组相比，每天BI 853520进行治疗，延迟了肿瘤的生长(中位TGI＝60％，p＝0.17)(图7，表5)。
表5：第14天的平均肿瘤体积，平均TGI和基于相对肿瘤体积的P值
Figure PCTCN2020129350-appb-000006
4.结论
BI853520可以抑制HMVII和GAK的CDX模型(两种带有NRAS突变的黑色素瘤模型)中的肿瘤生长。
通过引用将本发明中所提及的所有参考文献均完整合并入本文，就如同每一篇文献均单独列出一样。应理解，在阅读了本发明的公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落入本申请所附权利要求书所限定的范围内。

Claims (23)

  1. FAK抑制剂在制备用于治疗NRAS突变的肿瘤的药物中的用途。
  2. 如权利要求1所述的用途，其特征在于，所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐，优选为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
  3. 如权利要求1-2中任一项所述的用途，其特征在于，所述药物和有效量的第二治疗剂联用。
  4. 如权利要求1-3中任一项所述的用途，其特征在于，所述药物和放疗或者细胞治疗联用。
  5. 如权利要求1-4中任一项所述的用途，其特征在于，所述肿瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌、或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
  6. 如权利要求3所述的用途，其特征在于，所述第二治疗剂选自化疗剂、靶向治疗剂和免疫治疗剂中的一种或几种。
  7. 如权利要求3所述的用途，其特征在于，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米 地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种；进一步的选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗；更进一步的选自多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；更进一步的选自考比替尼。
  8. 一种治疗发生NRAS突变的肿瘤的方法，其包括向个体施用有效量的FAK抑制剂。
  9. 如权利要求8所述的方法，其特征在于，所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐，优选为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
  10. 如权利要求8-9中任一项所述的方法，其特征在于，其进一步包括向个体施用有效量的第二治疗剂。
  11. 如权利要求8-10中任一项所述的方法，其特征在于，其进一步包括放疗或者细胞治疗。
  12. 如权利要求8所述的方法，其特征在于，所述肿瘤为为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
  13. 如权利要求10所述的方法，其特征在于，所述第二治疗剂选自化疗剂、靶向治疗剂和免疫治疗剂中的一种或几种。
  14. 如权利要求10所述的方法，其特征在于，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比 星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种；进一步的选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗；更进一步的选自多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；更进一步的选自考比替尼。
  15. 如权利要求10所述的方法，其特征在于，所述FAK抑制剂和所述第二治疗剂同步、交替或序贯给药。
  16. 如权利要求11所述的方法，其特征在于，所述FAK抑制剂和放疗或细胞治疗同步、交替或序贯进行。
  17. 用于治疗NRAS突变的肿瘤的FAK抑制剂。
  18. 如权利要求17所述的FAK抑制剂，其特征在于，所述FAK抑制剂为BI853520、defactinib、GSK2256098、PF-00562271、VS-4718或其药学上可接受的盐，优选为BI853520或其药学上可接受的盐，尤其是BI853520酒石酸盐。
  19. 如权利要求17-18中任一项所述的FAK抑制剂，其特征在于，其进一步和有效量的第二治疗剂联用。
  20. 如权利要求17-19中任一项所述的FAK抑制剂，其特征在于，其进一步与放疗或者细胞治疗联用。
  21. 如权利要求17所述的FAK抑制剂，其特征在于，所述肿瘤为为霍奇金淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌、小细胞肺癌、肝细胞癌、胆管癌、骨髓增生异常综合征、急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、甲状腺癌、神经胶质瘤、结肠癌、直肠癌、结直肠癌、卵巢癌、膀胱癌、前列腺癌、乳腺癌、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、平滑肌肉瘤、血管肉瘤、神经母细胞瘤、肾细胞癌、头颈部癌、胃癌、食管癌、胃食管结合部癌、胸腺癌、胰腺癌、子宫内膜癌、宫颈癌、黑色素瘤、皮肤癌、生殖细胞癌、鼻咽癌、口咽癌、或喉癌；进一步的所述肿瘤为急性髓系白血病、黑色素瘤、甲状腺癌、结直肠癌、食道癌、肝细胞癌、卵巢癌、纤维肉瘤和胆管癌。
  22. 如权利要求19所述的FAK抑制剂，其特征在于，第二治疗剂选自化疗剂、靶向治疗剂和免疫治疗剂中的一种或几种。
  23. 如权利要求19所述的FAK抑制剂，其特征在于，所述第二治疗剂选自尼莫司汀、卡莫司汀、洛莫司汀、替莫唑胺、环磷酰胺、异环磷酰胺、甘磷酰芥、去氧氟鸟苷、多西氟鸟啶、氟尿嘧啶、巯嘌呤、巯唑嘌呤、巯鸟嘌呤、氟鸟苷、替加氟、吉西他滨、地西他滨、卡莫氟、羟基脲、甲胺喋呤、优氟定、卡培他滨、安西他滨、塞替哌、放线菌素D、阿霉素、脂质体阿霉素、柔红霉素、表柔比星、细裂霉素、平阳霉素、吡柔比星、戊柔比星、伊达比星、伊立替康、三尖衫酯碱、喜树碱、羟基喜树碱、托泊替康、长春瑞宾诺维本、紫杉醇、泰索帝、拓扑替康、长春碱、长春新碱、长春地辛、长春酰胺、长春花碱、替尼泊苷、依托泊苷、揽香烯、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酚、卡铂、顺铂、达卡巴嗪、奥沙利铂、乐沙定、可铂奥沙、米托蒽醌、丙卡巴肼、多西他赛、吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼、克唑替尼、色瑞替尼、艾乐替尼、拉帕替尼、依维莫司、帕博西尼、瑞博西尼、阿帕替尼、瑞戈非尼、索拉菲尼、舒尼替尼、替西罗莫司、乐伐替尼、帕唑替尼、阿雷替尼、阿希替尼、卡博替尼、曲美替尼、比美替尼、维罗非尼、达拉非尼、卡比替尼、凡德他尼、硼替佐米、帕布昔利布、来那度胺、伊沙佐米、伊马替尼、达沙替尼、博舒替尼、帕纳替尼、伊布替尼、艾代拉利司、贝利司他、罗米地辛、伏立诺他、奥拉帕尼、尼拉帕利、狄诺赛麦、维莫德吉、索尼德吉、鲁卡帕尼、布加替尼、比卡鲁胺、恩杂鲁胺、阿比特龙、阿贝西尼、阿帕他胺、阿柏西普、阿扎胞苷、博莱霉素、苯丁酸氮芥、阿糖胞苷、天冬酰胺酶、埃坡霉素、氟达拉滨、氟他胺、双氯乙基甲胺、帕利他塞、培美曲塞、雷替曲塞、耐昔妥珠单抗、贝伐珠单抗、雷莫芦单抗、Ado-曲妥珠单抗、帕托珠单抗、西妥昔单抗、帕尼单抗、阿利库单抗、德瓦鲁单抗、尼妥珠单抗、达雷木单抗、阿特珠单抗、 信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、德瓦鲁单抗、纳武利尤单抗、帕博利珠单抗中的一种或几种；进一步的选自地西他滨、吉西他滨、顺铂、卡铂、奥沙利铂、阿霉素、脂质体阿霉素、紫杉醇、多西他赛、曲美替尼、比美替尼、考比替尼、德瓦鲁单抗、阿特珠单抗、信迪利单抗、特瑞普利单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、帕博利珠单抗；更进一步的选自多西他赛、脂质体阿霉素、考比替尼、帕博利珠单抗、地西他滨；更进一步的选自考比替尼。
PCT/CN2020/129350 2019-11-18 2020-11-17 Fak抑制剂在制备用于治疗nras突变的肿瘤的药物中的用途 Ceased WO2021098679A1 (zh)

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KR1020227020144A KR20220101677A (ko) 2019-11-18 2020-11-17 Nras 돌연변이를 갖는 종양을 치료하기 위한 약물의 제조에서의 fak 억제제의 용도
BR112022009571A BR112022009571A2 (pt) 2019-11-18 2020-11-17 Uso de inibidor de fak na preparação de um fármaco para tratar tumores que têm mutação nras
EP20890277.5A EP4062914A4 (en) 2019-11-18 2020-11-17 USE OF AN FAK INHIBITOR IN THE PREPARATION OF A DRUG FOR THE TREATMENT OF TUMORS PRESENTING AN NRAS MUTATION
AU2020388848A AU2020388848A1 (en) 2019-11-18 2020-11-17 Use of FAK inhibitor in preparation of drug for treating tumors having NRAS mutation
PE2022000810A PE20221259A1 (es) 2019-11-18 2020-11-17 Uso del inhibidor de fak en la preparacion de un farmaco para el tratamiento contra tumores con mutacion nras
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