Use of FAK inhibitors in the preparation of medicaments for treating tumors with NRAS mutations

Abstract

The present invention relates to the use of a FAK inhibitor in a pharmaceutical preparation for preventing and / or treating tumors with NRAS mutations. The present invention also relates to a method for treating tumors with NRAS mutations, comprising administering an effective amount of a FAK inhibitor to an individual. The present invention also relates to a FAK inhibitor for treating tumors with NRAS mutations, wherein the FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718, or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention is in the field of medicinal chemistry. Specifically, the present invention relates to the use of FAK inhibitors in the preparation of medicaments for treating tumors with NRAS mutations. [Background technology]

[0002] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of focal adhesion complexes. FAK plays a key role in mediating integrin and growth factor signaling to regulate tumor cell invasion, proliferation, and survival. FAK is widely expressed and evolutionarily conserved. Studies over the past two decades have shown that FAK is overexpressed in various 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. This suggests that FAK plays an important role in adaptive resistance to immunotherapy and antitumor therapy. Both in vitro and in vivo preclinical studies have shown that blocking FAK has an antitumor effect. However, the inhibitory activity of FAK inhibitors on tumors varies greatly.

[0003] BI853520, a FAK inhibitor, has shown different antitumor activities in CDX (human tumor cell line-implanted mice) mouse models of 37 different tumors, with TGI (tumor growth inhibition) ranging from 0 to 107%. How to effectively use BI853520 to inhibit tumor growth is a technical problem that needs to be urgently solved in this field. Summary of the Invention [Problem to be solved by the invention]

[0004] In one aspect, the invention provides the use of a FAK inhibitor in the preparation of a medicament for treating a tumor harboring an NRAS mutation. [Means for solving the problem]

[0005] Optionally, the FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718, or a pharma- ceutically acceptable salt thereof.

[0006] Optionally, said FAK inhibitor is BI853520, or a pharma- ceutically acceptable salt thereof, in particular BI853520 tartrate.

[0007] The BI 853520 has the following structure: [ka]

[0008] Optionally, the pharmaceutical agent is used in combination with an effective amount of a second therapeutic agent.

[0009] Optionally, the medicament is combined with radiation therapy or cell therapy.

[0010] Optionally, 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 lymphoblastic 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 tumor, nasopharyngeal carcinoma, oropharyngeal carcinoma, or laryngeal carcinoma; further, the tumor is acute myeloid leukemia, melanoma, thyroid cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, ovarian cancer, fibrosarcoma, and cholangiocarcinoma.

[0011] Optionally, the second therapeutic agent is one or more selected from a chemotherapeutic agent, a targeted therapeutic agent, and an immunotherapeutic agent.

[0012] Optionally, the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, gliphosphine, doxifluridine, furtulon, fluorouracil, mercaptopurine, azathioprine, thioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, liposomal doxorubicin, daunorubicin, epinephrine, rifabutin ... Rubicin, mitomycin, pingyangmycin, pirarubicin, valrubicin, idarubicin, irinotecan, harringtonine, camptothecin, hydroxycamptothecin, topotecan, vinorelbine (navelbine), taxol, taxotere, hicamtine, vinblastine, vincristine, vindesine, vindesine sulfate, vinblastine, teniposide, etoposide, elemene, atamestane, anastrozole, aminoglutethimide, letrozole, formestane, megestrol, tamoxifen, asparaginase, carboplatin, cisplatin latin, dacarbazine, oxaliplatin, eloxatinib, eloxatinib, mitoxantrone, procarbazine, docetaxel, gefitinib, erlotinib, icotinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib, lapatinib, everolimus, palbociclib, ribociclib, apatinib, regorafenib, sorafenib, sunitinib, temsirolimus, lenvatinib, pazopanib, alectinib, axitinib, cabozantinib, trametinib, binimetinib, vemurafenib, dabrafenib, cobimetinib, ban Detanib, bortezomib, palbociclib, lenalidomide, ixazomib, imatinib, dasatinib, bosutinib, ponatinib, ibrutinib, idelalisib, belinostat, romidepsin, vorinostat, olaparib, niraparib, denosumab, vismodegib, sonidegib, rucaparib, brigutinib, bicalutamide, enzalutamide, abiraterone, abemaciclib, apalutamide, aflibercept, azacitidine, bleomycin, chlorambucil, cytarabine, asparaginase, epothilone, fludarabine, flutamide, mechlorethamine,One or more of the following are selected from the group consisting of paclitaxel, pemetrexed, raltitrexed, necitumumab, bevacizumab, ramucirumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, alirocumab, durvalumab, nimotuzumab, daratumumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, durvalumab, nivolumab, and pembrolizumab.

[0013] Optionally, the second therapeutic agent is one or more selected from decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, adriamycin, liposomal doxorubicin, taxol, docetaxel, trametinib, binimetinib, cobimetinib, durvalumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, nivolumab, and pembrolizumab.

[0014] Optionally, the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, decitabine.

[0015] Optionally, the second therapeutic agent is cobimetinib.

[0016] In another aspect, the invention provides a method of treating a tumor harboring an NRAS mutation, comprising administering to an individual an effective amount of a FAK inhibitor.

[0017] Optionally, said FAK inhibitor is BI853520 or defactinib, GSK2256098, PF-00562271, VS-4718, or a pharma- ceutically acceptable salt thereof, preferably BI853520, or a pharma- ceutically acceptable salt thereof, in particular BI853520 tartrate.

[0018] Optionally, the method further comprises administering to the individual an effective amount of a second therapeutic agent.

[0019] Optionally, it further includes radiation therapy or cell therapy.

[0020] Optionally, 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 lymphoblastic 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 tumor, nasopharyngeal carcinoma, oropharyngeal carcinoma, or laryngeal carcinoma; further, the tumor is acute myeloid leukemia, melanoma, thyroid cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, ovarian cancer, fibrosarcoma, and cholangiocarcinoma.

[0021] Optionally, the second therapeutic agent is one or more selected from a chemotherapeutic agent, a targeted therapeutic agent, and an immunotherapeutic agent.

[0022] Optionally, the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, gliphosphine, doxifluridine, futuron, fluorouracil, mercaptopurine, azathioprine, thioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, liposomal doxorubicin, daunorubicin, epirubicin, , mitomycin, pingyangmycin, pirarubicin, valrubicin, idarubicin, irinotecan, harringtonine, camptothecin, hydroxycamptothecin, topotecan, vinorelbine (navelbine), taxol, taxotere, hicamtine, vinblastine, vincristine, vindesine, vindesine sulfate, vinblastine, teniposide, etoposide, elemene, atamestane, anastrozole, aminoglutethimide, letrozole, formestane, megestrol, tamoxifen, asparaginase, carboplatin, cisplatin , dacarbazine, oxaliplatin, eloxatinib, eloxatinib, mitoxantrone, procarbazine, docetaxel, gefitinib, erlotinib, icotinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib, lapatinib, everolimus, palbociclib, ribociclib, apatinib, regorafenib, sorafenib, sunitinib, temsirolimus, lenvatinib, pazopanib, alectinib, axitinib, cabozantinib, trametinib, binimetinib, vemurafenib, dabrafenib, cobimetinib, bande Tanib, bortezomib, palbociclib, lenalidomide, ixazomib, imatinib, dasatinib, bosutinib, ponatinib, ibrutinib, idelalisib, belinostat, romidepsin, vorinostat, olaparib, niraparib, denosumab, vismodegib, sonidegib, rucaparib, brigutinib, bicalutamide, enzalutamide, abiraterone, abemaciclib, apalutamide, aflibercept, azacitidine, bleomycin, chlorambucil, cytarabine, asparaginase, epothilone, fludarabine, flutamide, mechlorethamine,One or more of the following are selected from the group consisting of paclitaxel, pemetrexed, raltitrexed, necitumumab, bevacizumab, ramucirumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, alirocumab, durvalumab, nimotuzumab, daratumumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, durvalumab, nivolumab, and pembrolizumab.

[0023] Optionally, the second therapeutic agent is selected from decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, adriamycin, liposomal doxorubicin, taxol, docetaxel, trametinib, binimetinib, cobimetinib, durvalumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, nivolumab, and pembrolizumab.

[0024] Optionally, the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, decitabine.

[0025] Optionally, the second therapeutic agent is cobimetinib.

[0026] Optionally, the second therapeutic agents are administered simultaneously, alternatingly, or sequentially.

[0027] Optionally, the FAK inhibitor is administered simultaneously, alternating, or sequentially with the radiation therapy or cell therapy.

[0028] In yet another aspect, the present invention provides a FAK inhibitor for treating tumors harboring NRAS mutations.

[0029] Optionally, said FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718, or a pharma- ceutically acceptable salt thereof, preferably BI853520, or a pharma- ceutically acceptable salt thereof, in particular BI853520 tartrate.

[0030] Optionally, it is further administered in combination with an effective amount of a second therapeutic agent.

[0031] Optionally, it is further combined with radiation therapy or cell therapy.

[0032] Optionally, 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 lymphoblastic 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 tumor, nasopharyngeal carcinoma, oropharyngeal carcinoma, or laryngeal carcinoma; further, the tumor is acute myeloid leukemia, melanoma, thyroid cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, ovarian cancer, fibrosarcoma, and cholangiocarcinoma.

[0033] Optionally, the second therapeutic agent is one or more selected from a chemotherapeutic agent, a targeted therapeutic agent, and an immunotherapeutic agent.

[0034] Optionally, the second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, gliphosphine, doxifluridine, futuron, fluorouracil, mercaptopurine, azathioprine, thioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, liposomal doxorubicin, daunorubicin, epirubicin, , mitomycin, pingyangmycin, pirarubicin, valrubicin, idarubicin, irinotecan, harringtonine, camptothecin, hydroxycamptothecin, topotecan, vinorelbine (navelbine), taxol, taxotere, hicamtine, vinblastine, vincristine, vindesine, vindesine sulfate, vinblastine, teniposide, etoposide, elemene, atamestane, anastrozole, aminoglutethimide, letrozole, formestane, megestrol, tamoxifen, asparaginase, carboplatin, cisplatin , dacarbazine, oxaliplatin, eloxatinib, eloxatinib, mitoxantrone, procarbazine, docetaxel, gefitinib, erlotinib, icotinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib, lapatinib, everolimus, palbociclib, ribociclib, apatinib, regorafenib, sorafenib, sunitinib, temsirolimus, lenvatinib, pazopanib, alectinib, axitinib, cabozantinib, trametinib, binimetinib, vemurafenib, dabrafenib, cobimetinib, bande Tanib, bortezomib, palbociclib, lenalidomide, ixazomib, imatinib, dasatinib, bosutinib, ponatinib, ibrutinib, idelalisib, belinostat, romidepsin, vorinostat, olaparib, niraparib, denosumab, vismodegib, sonidegib, rucaparib, brigutinib, bicalutamide, enzalutamide, abiraterone, abemaciclib, apalutamide, aflibercept, azacitidine, bleomycin, chlorambucil, cytarabine, asparaginase, epothilone, fludarabine, flutamide, mechlorethamine,One or more of the following are selected from the group consisting of paclitaxel, pemetrexed, raltitrexed, necitumumab, bevacizumab, ramucirumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, alirocumab, durvalumab, nimotuzumab, daratumumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, durvalumab, nivolumab, and pembrolizumab.

[0035] Optionally, the second therapeutic agent is selected from decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, adriamycin, liposomal doxorubicin, taxol, docetaxel, trametinib, binimetinib, cobimetinib, durvalumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, nivolumab, and pembrolizumab.

[0036] Optionally, the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, decitabine.

[0037] Optionally, the second therapeutic agent is cobimetinib.

[0038] definition The following terms and symbols used in this application have the meanings set forth below unless otherwise specified.

[0039] As used herein, the term "FAK inhibitor" refers to an effective inhibitor of FAK, which may be suitable for mammals, particularly humans.

[0040] As used herein, the term "NRAS" refers to a member of the RAS oncogene family, which further includes two other genes, KRAS and HRAS, which play important roles in cell division, cell differentiation, and apoptosis.

[0041] As used herein, the term "NRAS mutant" means that when a pathogenic mutation occurs in the NRAS gene, the N-Ras protein encoded thereby is in a state of continuous activation, leading to uncontrolled cell proliferation and further to the formation of tumors.

[0042] The term "treatment" as used herein refers to administering one or more pharmaceutical agents (particularly FAK inhibitors as described herein, particularly BI853520 or a pharma- ceutically acceptable salt thereof) to an individual having said disease or symptoms of said disease to cure, alleviate, mitigate, alter, treat, improve, ameliorate or affect said disease or symptoms of said disease. In some embodiments, said disease is a tumor or cancer. In further embodiments, said disease is a cancer or tumor with NRAS mutation.

[0043] The term "tumor" as used herein refers to an abnormal lesion formed by the aberrant clonal proliferation of cells of local tissue caused by the loss of normal regulation of their proliferation at the genetic level under the action of various tumorigenic factors. 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 lymphoblastic 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 tumor, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; further, the tumors are acute myeloid leukemia, melanoma, thyroid cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, ovarian cancer, fibrosarcoma, and cholangiocarcinoma.

[0044] As used herein, the term "individual" refers to mammals and non-mammals. Mammals refer to any member of the mammalian species, including, but not limited to, humans; non-human primates, such as chimpanzees, 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, such as rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex. In some embodiments, an individual is a human.

[0045] As used herein, the term "pharmaceutical acceptable" means non-toxic, biologically tolerable, and suitable for administration to an individual.

[0046] As used herein, the term "pharmaceutically acceptable salt" refers to an acid addition salt of BI853520 that is non-toxic, biologically acceptable, and suitable for administration to an individual, such as, for example, acid addition salts formed by BI853520 with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and salts of the formula HOOC-(CH), such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts of the formula HOOC-(CH). 2 ) n These include, but are not limited to, acid addition salts formed by BI853520 with organic acids, such as salts formed with alkane-dicarboxylic acids, such as -COOH (n is 0-4), in some embodiments, the salt is a tartrate salt.

[0047] Additionally, pharma- ceutically acceptable acid addition salts can be prepared by dissolving the free base in a suitable solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds.Those skilled in the art can determine, without undue experimentation, various synthetic methods used to prepare non-toxic pharma- ceutically acceptable acid addition salts.

[0048] As used herein, the term "effective amount" generally refers to an amount sufficient to produce beneficial effects on an individual.The effective amount of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, clinical trials, etc.) taking into account the usual influencing factors (e.g., administration method, pharmacokinetics of the compound, severity and course of disease, individual medical history, individual health status, individual response to medicine, etc.).

[0049] The term "second therapeutic agent" as used herein refers to one or more pharmaceutical agents used to prevent and / or treat a disease. In some embodiments, the second therapeutic agent is one or more selected from chemotherapeutic agents, targeted therapeutic agents, and immunotherapeutic agents. In some embodiments, the second therapeutic agent is one or more selected from nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, gliphosphine, doxifluridine, furtulon, fluorouracil, mercaptopurine, azathioprine, thioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, cyclophosphamide ... riamycin, liposomal doxorubicin, daunorubicin, epirubicin, mitomycin, pingyangmycin, pirarubicin, valrubicin, idarubicin, irinotecan, harringtonine, camptothecin, hydroxycamptothecin, topotecan, vinorelbine (navelbine), taxol, taxotere, hicamtine, vinblastine, vincristine, vindesine, vindesine sulfate, vinblastine, teniposide, etoposide, elemene, atamestane, anastrozole, Aminoglutethimide, letrozole, formestane, megestrol, tamoxifen, asparaginase, carboplatin, cisplatin, dacarbazine, oxaliplatin, eloxatin, eloxatin, mitoxantrone, procarbazine, docetaxel, gefitinib, erlotinib, icotinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib, lapatinib, everolimus, palbociclib, ribociclib, apatinib, regorafenib, sorafenib, Phenib, sunitinib, temsirolimus, lenvatinib, pazopanib, alectinib, axitinib, cabozantinib, trametinib, binimetinib, vemurafenib, dabrafenib, cobimetinib, vandetanib, bortezomib, palbociclib, lenalidomide, ixazomib, imatinib, dasatinib, bosutinib, ponatinib, ibrutinib, idelalisib, belinostat, romidepsin, vorinostat, olaparib, niraparib, denosumab, vismodegib, sonidegib,One or more selected from rucaparib, brigatinib, bicalutamide, enzalutamide, abiraterone, abemaciclib, apalutamide, aflibercept, azacitidine, bleomycin, chlorambucil, cytarabine, asparaginase, epothilone, fludarabine, flutamide, mechlorethamine, paclitaxel, pemetrexed, raltitrexed, necitumumab, bevacizumab, ramucirumab, ado-trastuzumab emtansine, pertuzumab, cetuximab, panitumumab, alirocumab, dulvalumab, nimotuzumab, daratumumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, dulvalumab, nivolumab, pembrolizumab. Optionally, the second therapeutic agent is selected from decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, doxorubicin, liposomal doxorubicin, taxol, docetaxel, trametinib, binimetinib, cobimetinib, dulvalumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, nivolumab, pembrolizumab. Optionally, the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, decitabine; Optionally, the second therapeutic agent is cobimetinib.,

[0050] Furthermore, the active ingredient from which the second therapeutic agent is selected may have different names depending on the translation, but still refers to one active ingredient. For example, Cobimetinib may be translated into Chinese as [Chemical formula] or cobimetinib.

[0051] As used herein, the term "inhibition" refers to a decrease in the baseline activity of a biological activity or process.

[0052] Technical and scientific terms not specifically defined herein have meanings commonly understood by those skilled in the art to which the present invention pertains. [Brief description of the drawings]

[0053] [Figure 1] Figure 1 shows the effect of IL-3 on the antiproliferative effect of BI 853520 in Ba / F3-NRASG12D cell line. For BI853520, the IC50 increased from 3.4 to 15 μM after addition of IL-3 to the NRASG12D-transfected Ba / F3 cell line, indicating a more than four-fold increase in IC50. Statistical data were analyzed using GraphPadPrism6 software and Student's t-test. The threshold for statistically significant differences was set at P = 0.05. [Diagram 2] Figure 2 shows the changes in body weight, showing that the blank control animals lost 1.9%, the median body weight of animals treated with 6 mg / kg BI 853520 increased 4.9% (p=0.9966 compared to control), the median body weight of animals treated with 12.5 mg / kg BI 853520 increased 5.7% (p=0.9996 compared to control), the median body weight of animals treated with 25 mg / kg BI 853520 increased 9.4% (p=1.0000 compared to control), and the median body weight of animals treated with 50 mg / kg BI 853520 increased 8.3% (p=0.999 compared to control). [Diagram 3] Figure 3 shows HT-1080 tumor growth kinetics, showing that on day 13, the median tumor volume of the blank control group was 823 mm3, the median tumor volume of the tumors treated with 6 mg / kg BI 853520 was 322 mm3, the median tumor volume of the tumors treated with 12.5 mg / kg BI 853520 was 149 mm3, the median tumor volume of the tumors treated with 25 mg / kg BI 853520 was 15 mm3, and the median tumor volume of the tumors treated with 50 mg / kg BI 853520 was 322 mm3. [Figure 4]Figure 4 shows the KYSE-270 tumor growth kinetics. The median tumor volume in the control group increased from 179mm3 to 1032mm3, the median tumor volume treated with BI 853520 at 50mg / kg daily decreased from 175mm3 to 126mm3 compared to the control group, the treatment with Taxol at 10mg / kg once a week had no effect on tumor growth, the median tumor volume increased from 190mm3 to 1033mm3, and the combination treatment with BI 853520 at 50mg / kg once a day and Taxol at 10mg / kg once a week significantly delayed tumor growth, decreasing the median tumor volume from 173mm3 to 87mm3. [Diagram 5] Figure 5 shows the changes in body weight. The median body weight of the animals in the control group decreased by 10.3%, the median body weight of the animals treated with BI 853520 at 50 mg / kg daily increased by 2.8%, the median body weight of the animals treated with Taxol at 10 mg / kg weekly decreased by 9.7%, and the median body weight of the animals increased by 3.5% with combined treatment of BI 853520 at 50 mg / kg daily and Taxol at 10 mg / kg weekly compared to the control group. [Figure 6] Figure 6 shows GAK tumor growth kinetics. Daily BI 853520 treatment slowed tumor growth in the GAK model compared to the control group. [Figure 7] Figure 7 shows HMVII tumor growth kinetics. Daily BI 853520 treatment slowed tumor growth in the HMVII model compared to the control group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] Working Example The present invention will be further described below with reference to examples. These examples are used only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0055] Experimental methods for which specific conditions are not specified in the following examples can be carried out according to the normal conditions of this type of reaction or according to the conditions proposed by the manufacturer.

[0056] The experimental materials and reagents used in the following examples are commercially available unless otherwise specified.

[0057] The meanings of the abbreviations used in the examples are as follows. ATCC American Type Culture Collection CO 2 Carbon dioxide d Day FCS Fetal calf serum FBS Fetal bovine serum g Gram kg Kilogram l Liter mg Milligram ml Milliliter μl Microliter mM Millimole mm 3 Cubic millimeter GLP Good Laboratory Practice h Hour MCB Master Cell Bank mean Arithmetic mean MTD Maximum tolerated dose n Sample size PBS Phosphate buffer RPMI 1640 RPMI 1640 medium p.o. Oral administration qd Every day q7d Once every 7 days (once a week) s.c. Subcutaneous administration SD Standard deviation TGI Tumor growth inhibition WCB Working Cell Bank V rel Relative tumor volume (relative to day 1)

[0058] Example I: Correlation between antitumor activity of BI853520 and NRAS 1. Materials and Methods: 1.1. DNA constructs and retrovirus production Retroviral constructs expressing NRAS-G12D, KRAS4A-G12D, KRAS4B-G12D and NRAS-G12D-C181S as N-terminal GFP fusion proteins were prepared according to the methods described in Cuiffo B, Ren R. Palmitoylation of oncogenic NRAS is essential for leukemogenesis. Blood.,2010,115:3598-605 and Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res.,2007,67:7139-46. Retroviruses were prepared using Bosc23 cells and titers were measured as described in Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res., 2007, 67:7139-46.

[0059] 1.2. Cell culture and retroviral transduction The Ba / F3 cell line was obtained from ATCC in 2009 and cultured according to the method described in 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. 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 a source of IL-3 to a final concentration of 1 ng / ml. BA / F3 cells were retrovirally transduced according to the methods described in Parikh C, Subrahmanyam R, Ren R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res.,2007,67:7139-46, and Fredericks J, Ren R. The role of RAS effectors in BCR / ABL induced chronic myelogenous leukemia. Front Med China.,2013,7:452-61. After collecting stocks, cells were expanded and frozen at low passage rates (<3). Frozen cells were thawed and used in this study, and cell passages were limited to 15 times for all experimental procedures. All cells were regularly inspected to ensure mycoplasma freedom and healthy condition.

[0060] 1.3. Materials BI853520: Synthesized according to the method of patent WO2010058032.

[0061] 1.4. Antiproliferative tests In 100 μL of medium, NRAS G12DBa / F3 (Ba / F3-N) transfected with KRAS G12D Ba / F3 (Ba / F3-N) cells transfected with were seeded in 96-well cell culture cluster plates at a density of 5,000 cells per well. BI853520 was diluted 3-fold in 9-point concentrations using RPMI1640 and added to reach a 3-fold concentration gradient (final solvent concentration <1 / 1000) starting from 10 μmol / L depending on the volume of each well. PD0325901 was used as a positive control. After 48 hours of incubation, cell viability was measured using CellTiter Glo (Promega). Luminescence was detected using an Envision plate reader (PerkinElmer). The calculation method of Z-factor was as described in 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, and only data with Z-factors above 0.6 were used in the following analysis. Dose-response curves were fitted based on the relative percentage of live cells in a nonlinear fit (curve fitting) using GraphPad Prism 6 software (http: / / www.graphpad.com / scientific-software / prism / ). Data analysis and IC 50 The calculation used the internal software "Nonlinear regression (curve fitting)" and the equation "Log(inhibitor) vs. slope of response variable".

[0062] 2. Statistical analysis: Statistical data were analyzed using GraphPad Prism 6 software and Student's t-test. The threshold for statistically significant differences was set at P = 0.05.

[0063] 3. Results: Ba / F3 is a mouse bone marrow-derived cell line that depends on IL-3 for survival and proliferation and has been used in high-throughput assays for kinase drug discovery. This system was tested with oncogenic RAS and found to inhibit oncogenic NRAS (NRAS G12D We found that Ba / F3-NRAS IL-3-independent expression could convert Ba / F3 cells to be IL-3-independent. G12D Showing the antiproliferative effect of BI853520 on cell lines and IC 50 The IC value is 3.4 μM. 50 was increased more than fourfold after addition of IL-3, indicating that the inhibitory effect is related to NRAS.

[0064] Table 1: Ba / F3-NRAS G12D Influence of the addition or absence of IL-3 on the antiproliferative effect of BI853520 in cell lines [Table 1]

[0065] Example 2: Effect of BI853520 in a mouse model of human fibrosarcoma (cell line HT-1080) 1. Materials and Methods: Study design Median tumor volume: 70-130 mm 3 Treatment was started during Blank control group: 10 mice; treatment groups: 7 mice per group. Administered by gavage once daily. Blank control: 0.5% hydroxyethylcellulose BI 853520: 50mg / kg, 25mg / kg, 12.5mg / kg, 6mg / kg, Tumor volumes were measured three times a week and body weights were monitored daily. Evaluation of treatment outcome was based on the absolute volumes of individual tumors. Tolerability was assessed based on changes in body weight.

[0066] 1.2. Materials BI853520: Synthesized according to the method of patent WO201005832. The dry powder was suspended in 0.5% hydroxyethylcellulose to obtain the desired concentration for each assay. The pH was 3.5.

[0067] HT-1080 cells: HT-1080 cells harboring NRAS, CDKN2A, and IDH1 gene mutations were obtained from ATCC (CRL-121). Cells were cultured in T175 tissue culture flasks in DMEM + Glutamax supplemented with 10% heat-inactivated fetal bovine serum. Cells were maintained at 37°C, 5% CO in humidified air. 2 was cultivated in.

[0068] Mice: Athymic female BomTac, NMRI-Foxn1, approximately 6 weeks old nu Mice were purchased from Taconic, Denmark. After arrival in the animal room, mice were allowed to acclimate to the new environment for at least 3 days before the assay. The animals were kept under standard conditions (temperature: 21.5 ± 1.5 °C, humidity: 55 + 10%), with 5 mice in each group. They were fed standard diet and autoclaved tap water ad libitum. Each mouse was identified using a Datamars T-IS8010FDX-B transponder implanted subcutaneously in the neck area and a LabMaxII fixed reader. The cage card indicated the study number, animal identification number, compound and dose level, route of administration, and the dosing schedule of the animal throughout the assay.

[0069] 1.3. Establishment of random tumors: To establish subcutaneous tumors, HT-1080 cells were harvested by trypsinization, centrifuged, washed, and resuspended in ice-cold PBS+1x10 8 The cells were then suspended at 1 × 10 7 100 μl of cell suspension containing 10 cells was injected subcutaneously into the right flank of nude mice (one site per mouse). When tumors were established and reached a diameter of 5–8 mm (7 days after cell injection), mice were randomly assigned to treatment and control groups.

[0070] 1.4. Administration: BI853520 was suspended in 0.5% hydroxyethylcellulose and administered daily intragastrically via a gavage needle at a dose of 10 mL / Kg body weight.

[0071] 1.5. Monitoring Tumor Growth and Side Effects: The diameter of the tumor was measured with a caliper three times a week (Monday, Wednesday, and Friday). The volume of each tumor [unit: mm 3 ] is "Tumor volume = length x diameter 2 The mean age of the mice was 18 years and 19 years. ... 3 Animals bearing tumors larger than 1 were sacrificed prematurely for ethical reasons.

[0072] 2. Statistical analysis: At the end of the assay on day 13, tumor volume and body weight parameters were statistically evaluated. Absolute tumor volume and percentage change in body weight (relative to initial body weight on day 1) were used. A non-parametric approach was used to calculate the number of observations, median, minimum, and maximum. To easily describe the treatment effect, the median tumor volume of each treatment group T and the median tumor volume of the control group C were used to calculate the TGI from day 1 to day d. TGI = 100 × [(C d -C 1 )-(T d -T 1 )] / (C d -C 1 ) Here, C 1 , T 1 = Median tumor volume of control and treatment groups on day 1 of the assay. C d , C d = Median tumor volumes for control and treatment groups at the completion of the assay on day 13.

[0073] A one-sided descending Wilcoxon test was used to compare each dose of the test compound with the control group, with the reduction in tumor volume as the therapeutic effect and the weight loss as the side effect. P values ​​for tumor volume (efficacy parameter) were compared and adjusted for multiple comparisons according to Bonferroni-Holm, but the P values ​​for weight (tolerability parameter) were not adjusted to avoid overlooking possible side effects. The significance level was fixed at α = 5%. A p value (adjusted) of less than 0.05 was considered to indicate a statistically significant difference between groups, and a p value of 0.05 ≤ p value < 0.10 was considered an indicative difference. Statistical evaluation was performed using the software packages SAS version 9.2 (SAS Institute Inc., NC, USA) and Proc StatXact version 8.0 (Cytel Software, MA, USA).

[0074] 3. Results: 3.1. During the study period, the body weight of the animals in the blank control group decreased by 1.9% (Figure 2, Table 2), and on day 13, their median tumor volume was 823 mm 3 (Figure 3, Table 3). 3.2. When treated with BI 853520 at 50 mg / kg once daily, tumor shrinkage was observed in all animals (Figure 3, Table 3) with a TGI of 107% (p=0.0002). The median body weight of the animals increased by 8.3% (compared to the control group, p=0.999) (Figure 2, Table 2). 3.3. When treated with BI 853520 at 25 mg / kg once daily, the TGI was 113% (p=0.0002) and tumor shrinkage was observed in 6 animals (Figure 3, Table 3). The median body weight of the animals increased by 9.4% (compared to the control group, p=1.0000) (Figure 2, Table 2). 3.4. When treated with BI 853520 at 12.5 mg / kg once daily, the TGI was 94% (p=0.0002) and tumor shrinkage was observed in two animals (Figure 3, Table 3). The median body weight of the animals increased by 5.7% (compared to the control group, p=0.9996) (Figure 2, Table 2). 3.5. When treated with BI 853520 at 6 mg / kg once daily, the TGI was 70% (p=0.0004) and tumor shrinkage was observed in one animal (Figure 5, Table 3). The median body weight of the animals increased by 4.9% (compared to the control group, p=0.9966) (Figure 2, Table 2).

[0075] Table 2: Median body weight change at end of assay [Table 2]

[0076] Table 3: Median tumor volume [Table 3]

[0077] 4. Conclusion: In a human HT-1080 fibrosarcoma model, BI 853520 demonstrated statistically significant antitumor activity at all dose levels, with regressions observed in all treatment groups. Also, at the highest dose level, tumor volume reduction was observed in all animals. In previous studies, the highest daily dose was 100 mg / kg without limiting toxicity. Thus, significant efficacy was obtained at a dose at least 16-fold lower (6 mg / kg) than the MTD.

[0078] Example 3: Antitumor activity of BI853520 in a subcutaneous xenograft mouse model derived from the human esophageal cancer cell line KYSE-270 in NMRI nude mice 1. Materials and Methods 1.1. Model: Human esophageal cancer cell line KYSE-270 was subcutaneously xenografted into NMRI nude mice. 1.2. Test compound: BI853520: Synthesized according to the method of patent WO201005832. 1.3. Cells: KYSE-270 is an esophageal cancer cell line (Public Health England, Catalogue Number: 94072021). Cells were cultured at 37°C, 5% CO 2The cells were cultured in T175 tissue culture flasks containing 0.1% ethanol and 0.1% ethanol. The medium was RPMI1640 + HAM's F12 (1:1) supplemented with 2% FCS and 2 mM Glutamax. The cells were passaged three times a week at a ratio of 1:2. 1.4. Mice: Mice were 8-10 week old female mice (BomTac:NMRI-Foxn1) purchased from Taconic, Denmark. nu ). Upon arrival in the animal room, mice were allowed to acclimate for at least 5 days prior to the assay. Animals were kept under standard conditions (temperature: 21.5 ± 1.5 °C, humidity: 55 + 10%), with 7–10 mice in each group. They were fed standard chow and autoclaved tap water ad libitum. Each mouse was identified using a subcutaneous microchip implanted under isoflurane anesthesia. The cage card indicated the study number, animal identification number, compound and dose level, route of administration, and the dosing schedule of the animal throughout the assay. 1.5. Random tumor creation: To establish subcutaneous tumors, collect KYSE-270 cells by centrifugation, wash, and incubate at 5 × 10 7 The cells were then resuspended in PBS + 5% FCS at a concentration of 5 × 10 6 100 μl of cell suspension containing 10 cells was injected subcutaneously into the right flank of mice (one site per mouse). Tumors were established and grew to a volume ranging from 94 to 252 mm. 3 When the mice reached 1 h post-cell injection (13 days after cell injection), they were randomly assigned to treatment and control groups.

[0079] 1.6. Administration: BI 853520 was suspended in 0.5% hydroxyethylcellulose and administered daily intragastrically via a gavage needle. The dose was 10 mL / Kg body weight. Taxol (Paclitaxel) was dissolved in saline (0.9% NaCl) and administered intravenously at 10 mL / Kg body weight. The BI 853520 suspension could be used for up to 7 days. Taxol solution was stored at 6°C and used for up to 14 days.

[0080] 1.7. Monitoring of tumor growth and side effects: The diameter of the tumor was measured with a caliper three times a week. The volume of each tumor [mm 3 ] is "Tumor volume = length x diameter 2 The mean tumor diameter was calculated according to the formula: ×π / 6. To monitor side effects of the treatment, mice were checked daily for abnormalities and weighed three times a week. Animals with tumors larger than 1.5 cm in diameter, tumor necrosis, or a 20% weight loss were sacrificed for ethical reasons.

[0081] 2. Statistical analysis: Tumor volumes and body weights on day 13 were statistically evaluated. Animal number 1 (blank control group) was excluded from statistical evaluation due to weight loss and had to be sacrificed early (day 9). The measured tumor volumes were used as target variables for statistical analysis. The number of animals in each group, median tumor volumes, minimum and maximum tumor volumes were calculated. To easily describe the treatment effect, the TGI was calculated using the median tumor volumes of each treatment group T and the median tumor volumes of control group C. TGI = 100 × [(C d -C 1 )-(T d -T 1 )] / (C d -C 1 ) Here, C 1 , T 1 = Median tumor volume of control and treatment groups on day 1 of the assay. C d , C d = Median tumor volumes for control and treatment groups at the completion of the assay on day 13.

[0082] Comparisons were made using the Wilcoxon test. For body weight, the percentage change from the initial body weight on day 1 was used as the target variable for statistical analysis. The number of animals in each group, the median, minimum and maximum body weight changes were calculated.

[0083] One-tailed tests were performed to compare all treatment groups with the control group and observe the following: Reduction in tumor volume (inhibition of tumor growth, efficacy parameter) -Reduction in weight change (weight loss, tolerability parameter).

[0084] Within each subtopic, p values ​​of efficacy parameters were compared and adjusted according to Bonferroni-Holm in multiple iterations. p values ​​of tolerability parameters were kept constant to avoid overlooking possible side effects. The significance level was fixed at α = 5%. A p value (adjusted) less than 0.05 was considered to indicate a statistically significant difference between groups, and a p value of 0.05 ≤ p value < 0.10 was considered an indicative difference. Statistical evaluation was performed using the SAS software package, version 9.4 (SAS Institute Inc., Cary NC, USA).

[0085] 3. Results Tumor volume and body weight: By day 13, the median tumor volume in the control group was 179 mm 3 From 1032mm 3 (Figure 4). The median body weight of the control animals was reduced by 10.3% (Figure 5, Table 4). On day 9, one animal had to be sacrificed due to severe weight loss.

[0086] Treatment with BI 853520 at 50 mg / kg daily significantly delayed tumor growth compared to the control group (median TGI=106%, p=0.0003) (Figure 5, Table 4). At day 13, 6 out of 7 tumors had shrunk (Table 4). The median body weight of the animals increased by 2.8%, which was not significantly different from the control group (p=0.9999) (Figure 5, Table 4).

[0087] Treatment with 10 mg / kg taxol once a week had no effect on tumor growth compared to the control group (median TGI=2%, p=0.3788) (Figure 4, Table 4). On day 13, tumors in all animals had not shrunk (Table 4). Median body weight of animals was reduced by 9.7%, which was not significantly different from the control group (p=0.7320) (Figure 5, Table 4).

[0088] Compared to the control group, the combination of BI 853520 at 50 mg / kg once daily and Taxol at 10 mg / kg once weekly significantly delayed tumor growth (median TGI=110%, p=0.0003) (Figure 4, Table 4). On day 13, tumor shrinkage was observed in all animals (Table 4). The median body weight of the animals increased by 3.5%, which was not significantly different from the control group (p=1.0000) (Figure 5, Table 4).

[0089] Table 4: TGI, tumor shrinkage and body weight change in each group (day 13) [Table 4]

[0090] 4. Conclusion: In a subcutaneous xenograft model of the human esophageal cancer cell line KYSE-270, treatment with BI 853520 at 50 mg / kg and in combination with Taxol at 10 mg / kg demonstrated statistically significant inhibition of tumor growth and both were well tolerated.

[0091] Example 4: Tumor growth inhibitory effect of BI 853520 in HMVII and GAK CDX models (NRAS-mutated melanoma models) 1. Materials and Methods 1.1. Test compound: BI853520, synthesized according to the method of patent WO201005832. BI853520 was prepared in 0.5% hydroxyethylcellulose (Ashland).

[0092] 1.2. Cells: The melanoma cell line GAK was purchased from the JCRB Cell Bank, and HMVII cells were purchased from Sigma. GAK was derived from an inguinal lymph node of a vaginal melanoma patient, and HMVII was derived from a primary vaginal melanoma. GAK and HMVII cells were cultured at 37°C and 5% CO 2The cells were cultured in tissue culture flasks containing 0.1% ethanol. The media were Ham's F12 with 10% heat-inactivated FBS and Ham's F10 with 15% FBS, respectively. All media were supplemented with 100 U / mL penicillin, 100 mg / mL streptomycin, and 2 mM GlutaMAX. All cell culture reagents were purchased from GIBCO. Both HMVII and GAK cell lines harbor NRAS mutations at position Q61. Q61K HMVII and NRAS Q61L GAK.

[0093] 1.3. Mice: 4-week-old female BALB / c nude mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.). After arriving in the animal room, the mice were allowed to acclimate to the new environment for at least 2 weeks before the assay. The animals were kept under standard conditions (temperature: 21.5 ± 1.5 °C, humidity: 55 ± 10%). Standard diet and autoclaved tap water were provided ad libitum. All animal care and experimental procedures were carried out in accordance with the animal care ethical guidelines approved by the Medical Ethics Committee of Beijing Tumor Hospital and Institute.

[0094] 1.4. Establishment of random tumors: To establish subcutaneous tumors, HMVII and GAK cells were harvested by trypsinization, centrifuged, washed, and resuspended in ice-cold PBS + 5% FCS. 6 100 μl of cell suspension containing 10 cells was injected subcutaneously into the right flank of nude mice (one site per mouse). Tumors were established and had a median volume of approximately 400–600 mm. 3 When this was reached, the mice were randomly assigned to treatment and control groups.

[0095] 1.5. Administration: BI853520 was suspended in 0.5% hydroxyethylcellulose and administered daily intragastrically via a gavage needle at a dose of 10 mL / Kg body weight.

[0096] 1.6. Monitoring Tumor Growth: The diameter of the tumor was measured twice a week with a vernier caliper. The volume of each tumor [mm 3 ] is "Tumor volume = length x diameter 2 The tumor necrosis rate was calculated according to the formula: xπ / 6. Animals were sacrificed at the completion of the study, approximately 2 weeks after the start of treatment. 3 Animals bearing tumors larger than 1 were sacrificed prematurely for ethical reasons.

[0097] 2. Statistical analysis: Upon completion of the assay, tumor volumes were statistically evaluated and relative values ​​were used for tumor volumes. The number of observations, median, minimum and maximum tumor volumes were calculated. In order to rapidly observe the therapeutic effect, the following indexes were calculated: Relative tumor volume: (T / C)

number

[0098] 3.Results In the GAK model, daily BI 853520 treatment delayed tumor growth compared to the control group (median TGI=80%, p=0.03) (Figure 6, Table 5). In the HMVII model, daily BI 853520 treatment slowed tumor growth compared to the control group (median TGI=60%, p=0.17) (Figure 7, Table 5).

[0099] Table 5: Mean tumor volume, mean TGI and P-value based on relative tumor volume on day 14 [Table 5]

[0100] 4. Conclusion BI853520 is able to inhibit tumor growth in HMVII and GAK CDX models, two melanoma models that harbor NRAS mutations.

[0101] All references mentioned herein are incorporated by reference in their entirety as if each were individually set forth. After reading the present disclosure, those skilled in the art will understand that various changes or modifications may be made to the present invention, and that equivalents thereof are also within the scope defined by the appended claims of this application.

Claims

1. A pharmaceutical for treating a tumor having an NRAS mutation, comprising a FAK inhibitor, wherein the FAK inhibitor is BI853520 or a pharma- ceutically acceptable salt thereof.

2. The pharma- ceutically acceptable salt of BI853520 is BI853520 tartrate; The pharmaceutical composition according to claim 1.

3. In combination with an effective amount of a second therapeutic agent, The pharmaceutical composition according to claim 1 or 2.

4. It is characterized in that it is used in combination with radiation therapy or cell therapy, The pharmaceutical composition according to any one of claims 1 to 3.

5. 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 lymphoblastic 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 tumor, nasopharyngeal cancer, oropharyngeal cancer, or laryngeal cancer; The pharmaceutical composition according to any one of claims 1 to 4.

6. The tumor is acute myeloid leukemia, melanoma, thyroid cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, ovarian cancer, fibrosarcoma, or cholangiocarcinoma. The pharmaceutical composition according to any one of claims 1 to 4.

7. The second therapeutic agent is one or more selected from a chemotherapeutic agent, a targeted therapeutic agent, and an immunotherapeutic agent; The pharmaceutical composition according to claim 3.

8. The second therapeutic agent is selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, gliphosphine, doxifluridine, furtulon, fluorouracil, mercaptopurine, azathioprine, thioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, liposomal doxorubicin, daunorubicin, epirubicin, and mitomycin. , Pingyangmycin, Pirarubicin, Valrubicin, Idarubicin, Irinotecan, Harringtonine, Camptothecin, Hydroxycamptothecin, Topotecan, Vinorelbine (Navelbine), Taxol, Taxotere, Hicamtine, Vinblastine, Vincristine, Vindesine, Vindesine Sulfate, Vinblastine, Teniposide, Etoposide, Elemene, Atamestane, Anastrozole, Aminoglutethimide, Letrozole, Formestane, Megestrol, Tamoxifen, Asparaginase, Carboplatin, Cisplatin, Dacarbazine, Oxaliplatin, Eloxatin, Eloxatin, Mitoxantrone, Procarbazine, Docetaxel, Gefitinib, Erlotinib, Icotinib, Afatinib, Osimertinib, Crizotinib, Ceritinib, Alectinib, Lapatinib, Everolimus, Palbociclib, Ribociclib, Apatinib, Regorafenib, Sorafenib, Sunitinib, Temsirolimus, Lenvatinib, Pazopanib, Alectinib, Axitinib, Cabozantinib, Trametinib, Binimetinib, Vemurafenib, Dabrafenib, Cobimetinib, Vandetanib, Bortezomib, Mibu, palbociclib, lenalidomide, ixazomib, imatinib, dasatinib, bosutinib, ponatinib, ibrutinib, idelalisib, belinostat, romidepsin, vorinostat, olaparib, niraparib, denosumab, vismodegib, sonidegib, rucaparib, brigutinib, bicalutamide, enzalutamide, abiraterone, abemaciclib, apalutamide, aflibercept, azacitidine, bleomycin, chlorambucil, cytarabine, asparaginase, epothilone, fludarabine, flutamide, mechlorethamine, paclitaxel,one or more selected from the group consisting of pemetrexed, raltitrexed, necitumumab, bevacizumab, ramucirumab, adotrastuzumab, pertuzumab, cetuximab, panitumumab, alirocumab, durvalumab, nimotuzumab, daratumumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, durvalumab, nivolumab and pembrolizumab; The pharmaceutical composition according to claim 3.

9. The second therapeutic agent is one or more selected from the group consisting of decitabine, gemcitabine, cisplatin, carboplatin, oxaliplatin, adriamycin, liposomal doxorubicin, taxol, docetaxel, trametinib, binimetinib, cobimetinib, durvalumab, atezolizumab, sintilimab, toripalimab, camrelizumab, tislelizumab, nivolumab, or pembrolizumab. The pharmaceutical composition according to claim 3.

10. The second therapeutic agent is one or more selected from the group consisting of docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, or decitabine. The pharmaceutical composition according to claim 3.

11. The second therapeutic agent is cobimetinib. The pharmaceutical composition according to claim 3.

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