US20230145356A1 - Use of fak inhibitor in preparation of drug for treating tumors having nras mutation - Google Patents

Use of fak inhibitor in preparation of drug for treating tumors having nras mutation Download PDF

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US20230145356A1
US20230145356A1 US17/777,769 US202017777769A US2023145356A1 US 20230145356 A1 US20230145356 A1 US 20230145356A1 US 202017777769 A US202017777769 A US 202017777769A US 2023145356 A1 US2023145356 A1 US 2023145356A1
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cancer
carcinoma
therapeutic agent
tumor
fak inhibitor
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Zaiqi Wang
Jiangwei Zhang
Jun Jiang
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Inxmed Nanjing Co Ltd
Inxmed Beijing Co Ltd
Inxmed Shanghai Co Ltd
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Inxmed Beijing Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • 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
    • A61K31/444—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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 present disclosure belongs to the field of pharmaceutical chemistry, and particularly relates to use of an FAK inhibitor in the manufacture of a medicament for treating tumors having an NRAS mutation.
  • 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 signaling to regulate invasion, proliferation and survival of tumor cells.
  • FAK is widely expressed and evolutionarily conserved.
  • Studies in the past 20 years 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, which suggests that FAK plays an important role in adaptive resistance to immunotherapy and anti-tumor therapy. Both in vitro and in vivo preclinical studies have shown that blocking FAK has antitumor effects.
  • the inhibitory activity of FAK inhibitors against tumors varies widely.
  • BI853520 is a FAK inhibitor.
  • human tumor CDX Cell line-Derived Xenograft mice model of 37 different tumors
  • TGI tumor growth inhibition
  • the present disclosure provides use of a FAK inhibitor in the manufacture of a medicament for treating a tumor having an NRAS mutation.
  • 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 medicament is used in combination with an effective amount of a second therapeutic agent.
  • the medicament 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 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, stomach cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma or
  • the second therapeutic agent is one or more selected from chemotherapeutic agents, targeted therapeutic agents and immunotherapy agents.
  • the second therapeutic agent is one or more selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, glyfosfin, doxifluridine, Furtulon, fluorouraeil, mercaptopurine, azathioprine, tioguanine, 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, hydroxycamptothecine, topotecan
  • the second therapeutic agent is 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, and pembrolizumab.
  • the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, or decitabine.
  • the second therapeutic agent is cobimetinib.
  • the present disclosure also provides a method of treating a tumor having an NRAS mutation comprising administering to an individual an effective amount of a FAK inhibitor.
  • the FAK inhibitor is BI853520 or 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 method further comprises administering to the individual an effective amount of a second therapeutic agent.
  • the method 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 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, stomach cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma or
  • the second therapeutic agent is one or more selected from chemotherapeutic agents, targeted therapeutic agents and immunotherapy agents.
  • the second therapeutic agent is one or more selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, glyfosfin, doxifluridine, Furtulon, fluorouraeil, mercaptopurine, azathioprine, tioguanine, 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, hydroxycamptothecine, topotecan
  • the second therapeutic agent is 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, and pembrolizumab.
  • the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, or decitabine.
  • the second therapeutic agent is cobimetinib.
  • the second therapeutic agent is administered simultaneously, alternately or sequentially.
  • the FAK inhibitor and radiotherapy or cell therapy are performed simultaneously, alternately or sequentially.
  • the present disclosure provides a FAK inhibitor for the treatment of a tumor having an NRAS mutation.
  • 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 FAK inhibitor is further used in combination with an effective amount of a second therapeutic agent.
  • the FAK inhibitor is further 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 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, stomach cancer, esophageal cancer, gastroesophageal junction cancer, thymic cancer, pancreatic cancer, endometrial cancer, cervical cancer, melanoma, skin cancer, germ cell carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma or
  • the second therapeutic agent is one or more selected from chemotherapeutic agents, targeted therapeutic agents and immunotherapy agents.
  • the second therapeutic agent is one or more selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, glyfosfin, doxifluridine, Furtulon, fluorouraeil, mercaptopurine, azathioprine, tioguanine, 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, hydroxycamptothecine, topotecan
  • the second therapeutic agent is 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, and pembrolizumab.
  • the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, or decitabine.
  • the second therapeutic agent is cobimetinib.
  • FAK inhibitor refers to a potent inhibitor of FAK, which may be suitable for mammals, particularly humans.
  • NRAS refers to an oncogene that is a member of the RAS oncogene family which also includes two other genes: KRAS and HRAS. These genes play important roles 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, resulting in uncontrolled cell proliferation and tumor formation.
  • treating refers to the administration of one or more drugs, particularly a FAK inhibitor described herein, especially BI853520 or a pharmaceutically acceptable salt thereof, to an individual with a disease or symptoms of said disease, to cure, alleviate, reduce, alter, remedy, ameliorate, improve or affect the disease or the symptoms of the disease.
  • the disease is a tumor or cancer.
  • the disease is a cancer or tumor having an NRAS mutation.
  • tumor refers to an abnormal lesion formed by abnormally clonal proliferation of cells of local tissues which lose the normal regulation on their growth at the gene 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, stomach cancer, esophageal cancer, gastroesoph
  • the term “individual” refers to mammals and non-mammals. Mammals means any member of the mammalian class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including 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, the individual is a human.
  • pharmaceutically acceptable means non-toxic, biologically tolerable and suitable for administration to an individual.
  • the term “pharmaceutically acceptable salt” refers to an acid addition salt of BI853520 that is non-toxic, biologically tolerable and suitable for administration to an individual.
  • the “pharmaceutically acceptable salt” includes, but are not limited to, acid addition salts formed by BI853520 with an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and acid addition salts formed by BI853520 with an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts with alkane-dicarboxylic acid of formula HOOC—(CH 2 ) n —COOH (wherein
  • a pharmaceutically acceptable acid addition salt may be produced 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, a variety of synthetic methods, which are used to prepare non-toxic pharmaceutically acceptable acid addition salts.
  • the term “effective amount” refers to an amount sufficient to generally bring about a beneficial effect in an individual.
  • the effective amount of the compounds of the present disclosure may be ascertained by conventional methods (such as modeling, dose escalation studies or clinical trials), and by taking into consideration conventional influencing factors (such as the mode of administration, the pharmacokinetics of the compound, the severity and course of the disease, the individual's medical history, the individual's health status and the individual's response to drugs).
  • second therapeutic agent refers to one or more drugs used to prevent and/or treat diseases.
  • the second therapeutic agent is one or more selected from chemotherapeutic agents, targeted therapeutic agents and immunotherapeutic agents.
  • the second therapeutic agent is one or more selected from the group consisting of nimustine, carmustine, lomustine, temozolomide, cyclophosphamide, isocyclophosphamide, glyfosfin, doxifluridine, Furtulon, fluorouraeil, mercaptopurine, azathioprine, tioguanine, floxuridine, tegafur, gemcitabine, decitabine, carmofur, hydroxyurea, methotrexate, UFT, capecitabine, ancitabine, thiotepa, actinomycin D, adriamycin, liposomal doxorubicin, daunorubicin, epirubici
  • 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.
  • the second therapeutic agent is docetaxel, liposomal doxorubicin, cobimetinib, pembrolizumab, or decitabine.
  • the second therapeutic agent is cobimetinib.
  • the drug substances from which the second therapeutic agent is selected may be slightly different in names due to different translations, but they still refer to one drug substance, for example: cobimetinib may be translated into Chinese as Ka Bi Ti Ni or Kao Bi Ti Ni.
  • inhibitor refers to a reduction in the baseline activity of a biological activity or process.
  • FIG. 1 shows influence of IL-3 on the antiproliferative effect of BI 853520 in the Ba/F3-NRAS G12D cell line. It illustrates that for BI853520, the IC 50 was increased from 3.4 to 15 ⁇ M after addition of IL-3 in NRAS G12D -transfected Ba/F3 cell line (increased by more than 4-fold).
  • FIG. 3 shows HT-1080 tumor growth kinetics. It illustrates that on day 13, the median tumor volume of the control group was 823 mm 3 ; the median tumor volume of the group treated with BI 853520 at 6 mg/kg was 322 mm 3 ; the median tumor volume of the group treated with BI 853520 at 12.5 mg/kg was 149 mm 3 ; the median tumor volume of the group treated with BI 853520 at 25 mg/kg was 15 mm 3 ; and the median tumor volume of the group treated with BI 853520 at 50 mg/kg was 322 mm 3 .
  • FIG. 4 shows KYSE-270 tumor growth kinetics, which illustrates the median tumor volume increased from 179 mm 3 to 1032 mm 3 in the control group.
  • the median tumor volume of the group treated with 50 mg/kg BI 853520 per day decreased from 175 mm 3 to 126 mm 3 .
  • Treatment with 10 mg/kg paclitaxel once a week had no effect on tumor growth, in which the median tumor volume increased from 190 mm 3 to 1033 mm 3 .
  • the combination therapy of 50 mg/kg BI 853520 once a day with 10 mg/kg paclitaxel once a week significantly delayed tumor growth, with the median tumor volume decreased from 173 mm 3 to 87 mm 3 .
  • FIG. 5 shows changes in body weight. It illustrates that animals in the control group had a 10.3% reduction in the median body weight, and compared to the control group, animals treated with 50 mg/kg BI 853520 daily had a 2.8% increase in the median body weight, animals treated with 10 mg/kg paclitaxel once a week had a 9.7% reduction in the median body weight, and animals treated with the combination therapy of 50 mg/kg BI 853520 once daily with 10 mg/kg paclitaxel once a week had a 3.5% increase in the median body weight.
  • FIG. 6 shows GAK tumor growth kinetics. It illustrates that in the GAK model, daily treatment with BI 853520 delayed tumor growth compared to the control group.
  • FIG. 7 shows HMVII tumor growth kinetics. It illustrates that in the HMVII model, daily treatment with BI 853520 delayed tumor growth compared to the control group.
  • Retroviral constructs expressing NRAS-G12D, KRAS4A-G12D, KRAS4B-G12D, and NRAS-G12D-C1815 as N-terminal GFP fusion proteins were prepared according to a method as 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 by using Bosc23 cells and the titre determination was performed by the method 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.
  • the Ba/F3 cell line was obtained from ATCC in 2009, and cultured according to a 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 including 10% FBS and supplemented with 15% WEHI-3 conditioned medium or recombinant IL-3 (Roche) as a source of IL-3 at a final concentration of 1 ng/ml.
  • BA/F3 cells were transduced with retrovirus according to a method 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 and Fredericks J, Ren R. The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia. Front Med China., 2013, 7: 452-61. Upon receipt of the original stock, cells were expanded and frozen at a low passage rate ( ⁇ 3). Frozen cells were thawed and used in this study, with cell passages limited to 15 for all experimental procedures. All cells were tested regularly to ensure freedom and maintenance in a normal state of mycoplasma.
  • NRAS G12D -transfected Ba/F3 (Ba/F3-N) or KRAS G12D -transfected Ba/F3 (Ba/F3-N) cells were seeded into 96-well cell culture cluster plate in 100 ⁇ L of medium at a density of 5,000 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 to reach a 3-fold concentration gradient (final solvent concentration ⁇ 1/1000).
  • 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).
  • Ba/F3 is a murine marrow-derived cell line depending on IL-3 for survival and proliferation, and has been successfully used in high-throughput assays for kinase drug discovery.
  • NRAS G12D oncogenic NRAS
  • FIG. 1 and Table 1 show the antiproliferative effect of BI853520 on Ba/F3-NRAS G12D cell line with IC 50 value of 3.4 ⁇ M. The IC 50 increased more than 4-fold after the addition of IL-3, indicating that the inhibitory effect was related to NRAS.
  • Treatment began when the median tumor volume was between 70-130 mm 3 .
  • mice 10 mice in the control group, and 7 mice in the treatment group.
  • BI 853520 50 mg/kg, 25 mg/kg, 12.5 mg/kg, 6 mg/kg,
  • Tumor volume was measured 3 times a week and body weight was monitored daily.
  • Evaluation of treatment outcome was based on absolute volume of individual tumors.
  • BI853520 synthesized according to the method in the patent WO2010058032.
  • the dry powder was suspended in 0.5% hydroxyethyl cellulose to obtain the desired concentration for each assay.
  • the pH of this formulation was 3.5.
  • HT-1080 cells HT-1080 cells carrying NRAS, CDKN2A and IDH1 gene mutations were obtained from ATCC (CRL-121). Cells were grown in T175 tissue culture flasks with DMEM+Glutamax supplemented with 10% heat-inactivated fetal bovine serum as medium. Cells were cultured at 37° C. and 5% CO 2 in humidified air.
  • mice Athymic female BomTac, approximately 6-week-old NMRI-Foxn1 nu mice were purchased from Taconic, Denmark. After arriving in the animal room, mice were acclimated to the new environment for at least 3 days before being used for assay. The animals were housed under standard conditions (temperature 21.5 ⁇ 1.5° C. and 55 ⁇ 10% humidity) with 5 mice in each group. A standard diet and autoclaved tap water were provided for ad libitum feeding. A Datamars T-IS 8010 FDX-B transponder implanted subcutaneously in the neck region and a LabMax II fixed reader were used to identify each mouse. The cage card showed study number, animal identification number, compound and dose level, route of administration, and dosing schedule for animals throughout the assay.
  • HT-1080 cells were harvested by trypsinization, centrifuged, washed and suspended in ice-cold PBS+1 ⁇ 10 8 cells/ml. Then 100 ⁇ l of cell suspension containing 1 ⁇ 10 7 cells was injected subcutaneously into the right flank of nude mice (1 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 the treatment group and the control group.
  • BI853520 was suspended in 0.5% hydroxyethyl cellulose, which was administered intragastrically through gavage needle every day, and the dosage was 10 mL/Kg.
  • Tumor diameters were measured with calipers three times a week (Monday, Wednesday, and Friday).
  • Animals were sacrificed at the end of the study (approximately two weeks after the start of treatment). During the study, animals with tumor necrosis or tumors larger than 2000 mm 3 were sacrificed ahead of schedule for ethical reasons.
  • TGI 100 ⁇ [( C d ⁇ C 1 ) ⁇ ( T d ⁇ T 1 )]/( C d ⁇ C 1 )
  • C 1 , T 1 median tumor volume in control and treatment groups at the start of the assay (day 1).
  • C d , T d median tumor volume in control and treatment groups at the end of the assay (day 13).
  • Each dose of test compound was compared to the control group using a one-sided descending wilcoxon test, taking reduction in tumor volume as a treatment effect and weight loss as a side effect.
  • a p-value (adjusted) of less than 0.05 was considered to show a statistically significant difference between groups, and 0.05 ⁇ p-value ⁇ 0.10 was considered as an indicative difference.
  • Statistical evaluations were performed using the software packages SAS version 9.2 (SAS Institute Inc., Cary, N.C., USA) and Proc StatXact version 8.0 (Cytel Software, Cambridge, Mass., USA).
  • BI 853520 demonstrated statistically significant antitumor activity at all dose levels, and regression was observed in all the treatment groups; reduction in tumor volume was observed in all animals at the highest dose level. 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 times lower than the MTD (6 mg/kg).
  • Example 3 Antitumor Activity of BI 853520 in a Subcutaneous Xenograft Mouse Model Derived from the Human Esophageal Cancer Cell Line KYSE-270 in NMRI Nude Mice
  • Model Subcutaneous xenograft of 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). Cells were cultured in T175 tissue culture flasks containing 5% CO 2 at 37° C. The medium was RPMI 1640+HAM F12 (1:1) supplemented with 2% FCS and 2 mM Glutamax. Passage was performed three times a week at a ratio of 1:2.
  • mice were 8 to 10 week old female mice (BomTac: NMRI-Foxn1 nu ) purchased from Taconic, Denmark. Upon arrival in the animal room, the mice were allowed to acclimate for at least 5 days before being used for assay. The animals were housed under standard conditions (temperature: 21.5 ⁇ 1.5° C., humidity: 55+10%), 7 to 10 mice for each group. A standard diet and autoclaved tap water were provided for ad libitum feeding. A subcutaneous microchip implanted under isoflurane anesthesia was used to identify each mouse. The cage card showed study number, animal identification number, compound and dose level, route of administration, and dosing schedule for animals throughout the assay.
  • BI 853520 was suspended in 0.5% hydroxyethyl cellulose, which was administered intragastrically through gavage needle every day, and the dosage was 10 mL/Kg body weight. Paclitaxel was dissolved in saline (0.9% NaCl), which was administered intravenously in a volume of 10 ml/kg body weight. The suspension of BI853520 could be used for up to 7 days. Paclitaxel solution was stored at 6° C. and used for up to 14 days.
  • TGI 100 ⁇ [( C d ⁇ C 1 ) ⁇ ( T d ⁇ T 1 )]/( C d ⁇ C 1 )
  • C 1 , T 1 median tumor volume in control and treatment groups at the start of the assay (day 1).
  • the wilcoxon test was used for comparison.
  • body weight the percent change relative to initial body weight on day 1 was used as the target variable for statistical analysis.
  • the number of animals, and the median, minimum and maximum weight changes in each group were calculated.
  • p-values for the efficacy parameter were compared and adjusted for multiple times according to Bonferroni-Holm.
  • a p-value (adjusted) of less than 0.05 was considered to show a statistically significant difference between groups, and 0.05 ⁇ p-value ⁇ 0.10 was considered as an indicative difference.
  • Statistical evaluations were performed using the SAS software package version 9.4 (SAS Institute Inc., Cary N.C., USA).
  • Test compound BI853520, which was synthesized according to the method in the patent WO2010058032. BI853520 was 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 originated in the inguinal lymph nodes of patients with vaginal melanoma, whereas HMVII originated in primary vaginal melanoma. GAK and HMVII cells were cultured in tissue culture flasks containing 5% CO 2 at 37° C. The media were Ham's F12 containing 10% heat-inactivated FBS and Ham's F10 containing 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.
  • HMVII and GAK cell lines carried an NRAS mutation at the Q61 position.
  • HMVII NRAS Q61K
  • GAK NRAS Q61L
  • 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 being used for assay. The animals were housed under standard conditions (temperature: 21.5 ⁇ 1.5° C., humidity: 55 ⁇ 10%). A Standard diet and autoclaved tap water were provided ad libitum. 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 harvested by trypsinization, centrifuged, washed and resuspended in ice-cold PBS+5% FCS. Then 100 ⁇ l of the cell suspension containing 5 ⁇ 10 6 cells was injected subcutaneously into the right flank of nude mice (1 site per mouse). When tumors were well established and reached a median volume of approximately 400-600 mm 3 , mice were randomly assigned to the treatment group and the control group.
  • BI 853520 was formulated in 0.5% hydroxyethyl cellulose, which was intragastrically administered through gavage needle every day, and the dosage was 10 mL/Kg body weight.
  • Tumor volumes were statistically assessed at the end of the assay. For tumor volume, relative values were used.
  • T / C 100 * T d C d ;
  • TGI 100 ⁇ [( C d ⁇ C 1 ) ⁇ ( T d ⁇ T 1 )]/( C d ⁇ C 1 )
  • C 1 , T 1 mean relative tumor volume in control and treatment groups at the start of the assay (day 1);
  • a p-value (adjusted) of less than 0.05 was considered to show a significant difference between treatment groups, and 0.05 ⁇ p-value ⁇ 0.10 was considered as an indicative difference.
  • BI853520 can inhibit tumor growth in CDX models of HMVII and GAK (two melanoma models with an NRAS mutation).

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