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WO2000047205A1 - Inhibiteurs de tyrosine-kinases et methodes d'utilisation de tels inhibiteurs - Google Patents

Inhibiteurs de tyrosine-kinases et methodes d'utilisation de tels inhibiteurs Download PDF

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Publication number
WO2000047205A1
WO2000047205A1 PCT/US2000/003341 US0003341W WO0047205A1 WO 2000047205 A1 WO2000047205 A1 WO 2000047205A1 US 0003341 W US0003341 W US 0003341W WO 0047205 A1 WO0047205 A1 WO 0047205A1
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Prior art keywords
formula
tyrosine kinase
kinase inhibitor
comp2
compl
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English (en)
Inventor
Ramachandran Murali
Mark I. Greene
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University of Pennsylvania Penn
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University of Pennsylvania Penn
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Priority to AU28760/00A priority Critical patent/AU2876000A/en
Priority to US09/913,128 priority patent/US6740665B1/en
Publication of WO2000047205A1 publication Critical patent/WO2000047205A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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

Definitions

  • the present invention is related to tyrosine kinase inhibitors, pharmaceutical compositions that comprise the same, and methods of using tyrosine kinase inhibitors to inhibit elevated tyrosine kinase activity associated with tumors that express pi 85.
  • the present invention relates to methods of treating individuals who have cancer characterized by tumors with cells that express pi 85.
  • the erbB family of receptors includes erbBl (EGFR), erbB2 (pi 85), erbB3 and erbB4.
  • EGFR erbBl
  • erbB2 pi 85
  • erbB3 erbB4.
  • pi 85 The rat cellular protooncogene c-neu and its human counterpart c-erbB2 encode 185 kDa transmembrane glycoproteins termed pi 85.
  • Tyrosine kinase (tk) activity has been linked to expression of the transforming phenotype of oncogenic pi 85 (Bargmann et al, Proc. Natl. Acad. Sci. USA, 1988, 85, 5394; and Stern et al, Mol. Cell. Biol. 1988, 8, 3969. each of which is incorporated herein by reference).
  • Oncogenic neu was initially identified in rat neuroglioblastomas (Schechter et al. Nature. 1984. 312.
  • NIH3T3 cells Chazin et al, Oncogene, 1992, 7, 1859; DiFiore et al. , Science, 1987, 237, 178; and DiMarco et al. , Mol. Cell. Biol, 1990, 10, 3247, each of which is incorporated herein by reference).
  • NIH3T3 cells or NR6 cells which express cellular pi 85 at the level of 10 5 receptors/cell are not transformed (Hung et al, Proc. Natl. Acad. Sci.
  • cellular pi 85 and oncogenic pi 85 may both result in the transformation of cells.
  • Cellular pi 85 is highly homologous with EGFR (Schechter et al, Nature, 1984, 312, 513; and Yamamoto et al, Nature, 1986, 319, 230, each of which is incorporated herein by reference) but nonetheless is distinct. Numerous studies indicate that EGFR and cellular pi 85 are able to interact (Stern et al. , Mol. Cell. Biol. , 1988, 8, 3969; King et al, EMBO 1, 1988, 7, 1647; Kokai et al, Proc. Natl. Acad. Sci. USA, 1988, 85, 5389; and Dougall et al, J. Cell. Biochem., 1993, 53, 61 ; each of which is incorporated herein by reference).
  • Human pl85 forms heterodimers with either erbB3 or erbBA under physiologic conditions, primarily in cardiac muscle and the nervous system, particularly in development.
  • Cellular pi 85 proteins are found in adult secretory epithelial cells of the lung, salivary gland, breast, pancreas, ovary, gastrointestinal tract, and skin (Kokai et al. , Proc. Natl. Acad. Sci. USA. 1987, 84, 8498; Mori et al, Lab. Invest., 1989, 61, 93; and Press et al, Oncogene, 1990, 5, 953; each of which is incorporated herein by reference).
  • adenocarcinomas such as gastric (Akivama et al., Science, 1986, 232, 1644, which is incorporated herein by reference), lung (Kern et al, Cancer Res., 1990, 50, 5184, which is incorporated herein by reference) and pancreatic adenocarcinomas (Williams et al, Pathobiol, 1991, 59, 46, which is incorporated herein by reference).
  • the present invention relates to tyrosine kinase inhibitors having a structure of Formula 1, Formula 2, Formula 3, Formula 4 or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to pharmaceutical composition
  • pharmaceutical composition comprising: a pharmaceutically acceptable carrier or diluent; and, a tyrosine kinase inhibitor having a structure selected from the group consisting of Formula 1, Formula 2, Formula 3, Formula 4 and pharmaceutically acceptable salts thereof.
  • the present invention further relates to methods of treating mammals who have pi 85 tumors.
  • the method comprise the step of administering to the mammal an amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and, a tyrosine kinase inhibitor having a structure selected from the group consisting of Formula 1, Formula 2, Formula 3, Formula 4 and pharmaceutically acceptable salts thereof effective to reduce tumor growth.
  • the present invention further relates to methods of preventing pi 85 tumors in a mammal at an elevated risk of developing such tumors.
  • the method comprise the step of administering to the mammal a prophylactically effective amount of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier or diluent, and. a tyrosine kinase inhibitor having a structure selected from the group consisting of Formula 1,
  • Formula 2 Formula 3, Formula 4 and pharmaceutically acceptable salts thereof effective to reduce tumor growth.
  • pi 85 is meant to refer to the neu gene product and the erbB-2 gene product which are 185 kdalton receptor proteins as determined by carrying out electrophoresis on the glycoprotein and comparing its movement with marker proteins of known molecular weight, pi 85 has tyrosine kinases activity, forms homodimers with themselves and interacts with other members of the erbB family, such as erbB 1 (epidermal growth factor receptor or EGFR), erbB3 and erbB4 to form heterodimers.
  • erbB 1 epidermal growth factor receptor or EGFR
  • erbB3 and erbB4 to form heterodimers.
  • pi 85 tumors As used herein, the term "pi 85 tumors", “/lew-associated cancer”, ''neu- associated tumors” and “pl85-associated tumors” are used interchangably and are meant to refer to tumors with cells that express pi 85.
  • a pi 85 tumor may contain cells that express pi 85 and, additionally, other members of the erbB family, such as erbB 1 (EGFR), erbB3 and erbBA to form heterodimers and EGFR.
  • a pi 85 tumor may contain pi 85 homodimers and/or heterodimers including pl 85-EGFR heterodimers and/or pi 85-erbB3 heterodimers and/or pi 85-erbB4 heterodimers.
  • pi 85 tumors include many human adenocarcinomas such as some breast, ovary, lung, pancreas, salivary gland, kidney, prostate adenocarcinomas and some neuroblastoma.
  • pi 85-mediated cellular transformation is meant to refer to the cellular transformation that pi 85-associated tumor cells and neoplasms undergo and whose transformed phenotype can be arrested and/or reversed by tyrosine kinase inhibitors.
  • the term "high risk individual” is meant to refer to an individual who either a) has had a pi 85-associated tumor either removed or enter remission and who is therefore susceptible to a relapse or recurrence or b) has a genetic predisposition to develop pi 85 tumors.
  • Individual who have had pi 85-associated tumor either removed or enter remission can be readily identified through personal medical history.
  • Individuals who have a genetic predisposition to develop pi 85 tumors can be identified by those skilled in the art using various means such as by review of family medical history.
  • the individual can be prophylactically treated against tumors that they have been diagnosed as having had in order to combat a recurrence or tumor development.
  • the individual can be treated according to the present invention to prevent normal cells from transforming into tumor cells.
  • the term "therapeutically effective amount” is meant to refer to an amount of a compound which produces a medicinal effect observed as reduction or reverse in tumorigenic phenotype of tumor cells in an individual when a therapeutically effective amount of a compound is administered to an individual who is susceptible to or suffering from pi 85 tumors.
  • Therapeutically effective amounts are typically determined by the effect they have compared to the effect observed when a composition which includes no active ingredient is administered to a similarly situated individual.
  • prophylactically effective amount is meant to refer to an amount of a compound which produces a medicinal effect observed as the prevention of non-transformed cells from becoming transformed in an individual when a prophylactically effective amount of a compound is administered to an individual who is susceptible to pi 85 tumors.
  • Prophylactically effective amounts are typically determined by the effect they have compared to the effect observed when a composition which includes no active ingredient is administered to a similarly situated individual.
  • the present invention is useful to therapeutically treat an individual identified as suffering from pi 85-associated tumors in order to reverse the transformed phenotype of the tumor cells.
  • the present invention is useful to prophylactically treat an individual who is predisposed to develop pi 85-associated tumors or who has had pi 85- associated tumors and is therefore susceptible to a relapse or recurrence.
  • the present invention provides novel compounds which have tyrosine kinase inhibitor activity and a formula selected from the group consisting of Formula 1 , Formula 2, Formula 3 and Formula 4, as set forth in the section below entitled Formulae, or a pharmaceutically acceptable salt thereof.
  • the invention provides novel pharmaceutical compositions comprising tyrosine kinase inhibitors which can reduce the enhanced tyrosine kinase activity associated with pi 85 homodimers and pl85-EGFR heterodimers, pl 85-erbB3 heterodimers and pl85-erbB4 heterodimers.
  • the tyrosine kinase inhibitors included in the pharmacuetical compositions of the present invention have a formula selected from the group consisting of Formula 1, Formula 2, Formula 3 and Formula 4, as set forth in the section below entitled Formulae, or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 1 as set forth in the section below entitled Formulae.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 1 COMP11 (F, 1 ), COMP12 (F 2 '), COMP13 (F 3 '), COMP14 (F 4 '), COMP15 (F 5 '), or COMP16 (F 6 '), as set forth in the section below entitled Formulae, or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 2 as set forth in the section below entitled Formulae.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 2 COMP21 (F, 2 ), COMP22 (F 2 2 ), COMP23 (F 3 2 ), COMP24 (F 4 2 ), or COMP25 (F 5 2 ), as set forth in the section below entitled Formulae, or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 3 as set forth in the section below entitled Formulae.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 3 COMP31 (F, 3 ), COMP32 (F 2 3 ), COMP33 (F 3 3 ), or COMP34 (F 4 3 ), as set forth in the section below entitled Formulae.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 4 as set forth in the section below entitled Formulae.
  • the tyrosine kinase inhibitor in the pharmacuetical compositions of the present invention has a formula of Formula 4 COMP41 (F, 4 ), or COMP42 (F 2 4 ), as set forth in the section below entitled Formulae, or a pharmaceutically acceptable salt thereof.
  • the invention provides methods for treating mammals who have pi 85 tumors.
  • a tyrosine inhibitor according to Formula 1 , Formula 2, Formula 3 or Formula 4 is administered to the mammal in an amount effective to suppress tumor growth.
  • the tyrosine kinase inhibitor reduces tyrosine kinase activity and thus suppresses tumor growth.
  • the tyrosine kinase inhibitor is COMP1 1 (F, ').
  • the invention also provides novel therapeutic compositions for treating mammals who have pi 85 tumors.
  • the methods comprise admininstering to such mammals a therapetucially effective amount of a tyrosine kinase inhibitor according to Formula 1, Formula 2, Formula 3 or Formula 4.
  • the tyrosine kinase inhibitor is COMP11 (F, 1 ), COMP12 (TV), COMP13 (F 3 '), COMP14 (F 4 > ),
  • the method of the invention additionally includes the use of the tyrosine kinase inhibitors in combination with other methodologies to treat tumors.
  • the tyrosine kinase inhibitor is administered in conjunction with other chemotherapeutic agents.
  • the tyrosine kinase inhibitor is administered in conjunction with radiation therapy.
  • the tyrosine kinase inhibitor is administered in conjunction with other chemotherapeutic agents and radiation therapy.
  • the expression of pi 85 by cells of the tumor are identified prior to administration of the tyrosine kinase inhibitor.
  • samples of tumors may be removed such as biopsy samples and tested to identify the presence of pi 85 using pi 85-specific antibodies.
  • the antibodies are preferably monoclonal antibodies. Those having ordinary skill in the art can routinely generate antibodies specific for pi 85 such as by the method in Harlow and Lane, eds., Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory. Cold Spring Harbor, New York. 1988.
  • a general method for the production of monoclonal antibodies comprises the steps of immunizing an animal such as a mouse or rat with an antigen to which monoclonal antibodies are desired.
  • the animal After allowing time for the immune system to generate lymphocytes capable of producing antibodies to the antigen, the animal is sacrificed and a suspension of spleen cells is prepared. The spleen cells are then fused with myeloma cells by contacting them in the presence of a fusion promoter such as polyethylene glycol. A percentage of the cells fuse to produce hybridomas.
  • a fusion promoter such as polyethylene glycol.
  • a percentage of the cells fuse to produce hybridomas.
  • the earlier immunization of the animal from which the spleen cells were removed results in a number of lymphocytes which secrete antibody to the antigen of interest, a characteristic that is transferred genetically to the hybridoma during fusion of the spleen and myeloma cells. Hybridomas secreting monoclonal antibody having the desired specificity are then isolated using routine screening techniques.
  • Antibodies against pi 85 are described in U.S. Patent No. 5,677,171 issued October 14, 1997, which is incorporated herein by reference, and U.S. Patent No. 5,705,157 issued January 6, 1998, which is incorporated herein by reference.
  • Peptidomimetics of antibodies against pi 85 which bind to pi 85 and which can be used to identify the presence of pi 85 are described in U.S. Patent No. 5,663,144 issued September 2, 1997, which is incorporated herein by reference.
  • Other methods for identifying tumors which express pi 85 may be designed routinely.
  • compositions comprising tyrosine kinase inhibitors of the present invention may be administered by any means that enables the active agent to reach the agent's site of action in the body of a mammal.
  • Pharmaceutical compositions of the present invention may be administered by conventional routes of pharmaceutical administration.
  • Pharmaceutical compositions may be administered parenterally, i.e., intratumor, intravenous, subcutaneous, intramuscular. Intravenous and intratumor administration are preferred routes.
  • the pharmaceutical compositions are administered orally.
  • Pharmaceutical compositions are administered to the mammal for a length of time effective to reduce tumor size and as needed to maintain regression of the tumor.
  • Pharmaceutical compositions of the present invention may be administered either as individual therapeutic agents or in combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Dosage varies depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dosage of active ingredient can be about 0.001 to 1 grams per kilogram of body weight, in some embodiments about 0.1 to 100 milligrams per kilogram of body weight.
  • ordinarily dosages are in the range of 0.5 to 50 milligrams per kilogram of body weight, and preferably 1 to 10 milligrams per kilogram per day.
  • the pharmaceutical compositions are given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
  • Dosage forms (composition) suitable for internal administration generally contain from about 1 milligram to about 500 milligrams of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95 by weight based on the total weight of the composition.
  • individuals may be boosted by readministration. In some preferred embodiments, multiple administrations are performed.
  • compositions may be formulated by one having ordinary skill in the art with compositions selected depending upon the chosen mode of administration. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field, which is incorporated herein by reference.
  • the compound can be formulated as a solution, suspension, emulsion or lyophilized powder in association with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle examples include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used.
  • the vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g. buffers and preservatives).
  • the formulation is sterilized by commonly used techniques.
  • a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of active ingredient in 0.9% sodium chloride solution.
  • the composition is administered to tissue of an individual by topically or by lavage.
  • the compounds may be formulated as a cream, ointment, salve, douche, suppository or solution for topical administration or irrigation.
  • Formulations for such routes administration of pharmaceutical compositions are well known.
  • additives for isotonicity can include sodium chloride, dextrose, mannitol, sorbitol and lactose.
  • isotonic solutions such as phosphate buffered saline are used.
  • Stabilizers include gelatin and albumin.
  • a vasoconstriction agent is added to the formulation.
  • the pharmaceutical preparations according to the present invention are preferably provided sterile and pyrogen free.
  • a pharmaceutically acceptable formulation will provide the active ingredient(s) in proper physical form together with such excipients, diluents, stabilizers, preservatives and other ingredients as are appropriate to the nature and composition of the dosage form and the properties of the drug ingredient(s) in the formulation environment and drug delivery system.
  • the invention relates to methods of treating patients suffering from human adenocarcinomas which are pi 85-associated cancers such as gastric, lung and pancreatic adenocarcinomas and human breast and ovarian carcinomas as well as human breast and prostate cancer which are pi 85-associated cancer. In some embodiments, the invention relates to methods of preventing these pi 85-associated cancers in high risk individuals. In some embodiments, the invention relates to methods of preventing these pi 85-associated cancers in high risk individuals.
  • the invention relates to methods of treating patients suffering from human epithelial malignancies erythroid leukemia, fibrosarcoma, angiosarcoma and melanoma. In some embodiments, the invention relates to methods of preventing these pi 85-associated cancers in high risk individuals.
  • the patient is treated with radiation or other chemotherapy in conjunction the administration of pharmaceutical compositions according to the invention. The use of multiple therapeutic approaches provides the patient with a broader based intervention.
  • the individual in combination with administration of the composition that comprises the tyrosine kinase inhibitor, the individual is then administered a cytotoxic chemotherapeutic agent.
  • the individual in combination with administration of the composition that comprises the tyrosine kinase inhibitor, the individual is exposed to chemotherapeutic agents and, additionally, to a therapeutic amount of gamma radiation.
  • Chemotherapy approaches include administration of cytotoxic and or cytostatic agents. Chemotherapeutics are delivered according to standard protocols using standard agents, dosages and regimens. In some embodiments, the chemotherapeutic is selected from the group consisting of: cisplatin, doxirubicin, danurubicin, tamoxiphen, taxol, and methotrexate.
  • chemotherapeutics useful in the present invetion include, but are not limited to: cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, and other nitrogen mustards (e.g. cyclophosphamide), vindesine (and other vinca alkaloids), mitomycin and bleomycin.
  • chemotherapeutics may be administered to patients being treated or who have treated for tumors that express pl85.
  • radiotherapy follows administration of pharmaceutical compositions according to the invention.
  • the radiation therapy using gamma radiation is provided following administration of compositions which convert radiation resistant tumors, radiation sensitive.
  • the individual is then exposed to a therapeutic amount of gamma radiation.
  • Gamma radiation is delivered according to standard radiotherapeutic protocols using standard dosages and regimens. Those skilled in the art can readily formulate an appropriate radiotherapeutic regimen. Carlos A Perez & Luther W Brady: Principles and Practice of Radiation Oncology, 2nd Ed.
  • treatment with pharmaceutical compositions according to the invention is preceded by surgical intervention.
  • the present invention provides anti-cancer gene therapy treatment to treat residual, local disease, as a therapeutic adjuvant in combination with preexisting treatments. Delivery is local at the time of surgery, most likely after the resection of all gross disease.
  • the pharmaceutical compositions are administered locally at the site of the tumor. In some embodiments, the pharmaceutical compositions are administered directly into the tumor cells and the tissue immediately surrounding the tumor.
  • the present invention relates to methods of preventing tumors in any patient population identified as being susceptible to pi 85 tumors, it is particularly useful in high risk individuals who, for example, have a family history of cancer characterized by such tumors or those who show a genetic predisposition. Additionally, the present invention is particularly useful to prevent recurrence of such tumors in patients who have had such tumors removed by surgical resection or who have been diagnosed as having such cancer in remission.
  • the pellet was redissolved in 1.5 ml of membrane buffer (40 mM NaCl, 0.1 mM EDTA, 20 mM HEPES (pH 6.8), 2 mM PMSF, and 5 mM Na pyrophosphate) then layered over a (20%-37%) sucrose solution in membrane buffer and centrifuged at 22000 rpm for 18 hours at 2°C by using a Beckman SW50.1 rotor.
  • the membrane-rich interface was removed in 1 ml total volume, diluted with 10 ml of membrane buffer, and was recentrifuged at 40000 rpm for 60 minutes by using an SW40.1 rotor exactly as described in Zick et al, Biochem. Biophys. Res.
  • Membrane concentrations were determined by the method of Bradford as described in Gaulton et al, J. Immunol, 1986, 7. 2470, which is incorporated herein by reference. Dilutions of membranes were incubated in quadruplicate in the presence or absence of synthetic polypeptide containing tyrosine as a specific indicator of tyrosine phosphorylation.
  • Kinase reaction buffer 50 ⁇ l of 0.1 M Hepes pH 7.3, 10 mM MgCl 2 , 5 mM MnCl 2 , 50 ⁇ M Na 3 VO 4 were incubated in the presence of ATP (1 ⁇ Ci of gamma [ 32 P]ATP; Amersham) for 5 minutes at room temperature.
  • membrane proteins were incubated in 50 ⁇ l of 10 mM HEPES pH 7.2, containing 10 mM MgCl 2 , 100 ⁇ M Na 3 VO 4 , and 150 ⁇ M ( 10 ⁇ Ci) [ 32 P] ATP for 15 minutes at room temperature in the presence (specific) or absence (background) of poly glu:tyr substrate at 2.5 mg/ml. Reactions were stopped by the addition of EDTA to 50 mM final concentration and cold excess ATP and samples were spotted onto Whatman glass fiber filter paper.

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Abstract

L'invention se rapporte à des inhibiteurs de tyrosine-kinases et à une composition pharmaceutique contenant de tels inhibiteurs. Elle se rapporte également à des méthodes de traitement de mammifères présentant des tumeurs p185 ainsi qu'à des méthodes de prévention des tumeurs p185 chez des mammifères ayant un risque élevé de développer ce genre de tumeur. Les méthodes en question consistent à administrer à un mammifère des quantités efficaces de compositions pharmaceutiques comportant un excipient pharmaceutiquement acceptable ou un diluant et un inhibiteur de tyrosine-kinases.
PCT/US2000/003341 1999-02-10 2000-02-09 Inhibiteurs de tyrosine-kinases et methodes d'utilisation de tels inhibiteurs Ceased WO2000047205A1 (fr)

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KR20030066927A (ko) * 2002-02-06 2003-08-14 구자영 쿠르쿠민과 5-프루오로유라실로 이루어진 항암제 및 이항암제의 용도
CN102180849A (zh) * 2011-03-24 2011-09-14 广东工业大学 一种二芳基二烯环酮衍生物及其制备方法与应用
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WO2018049296A1 (fr) * 2016-09-12 2018-03-15 Padlock Therapeutics, Inc. Inhibiteurs hétéroaryles de pad4
CN113908146A (zh) * 2021-07-16 2022-01-11 温州医科大学附属第一医院 5-溴刺甘草查尔酮化合物在制备抗癌药物中的应用

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WO2002098425A1 (fr) * 2001-06-04 2002-12-12 Cytovia, Inc. Quinolinones 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1h)- substituees, et analogues utilises comme activateurs de caspases et inducteurs d'apoptose, et utilisation y relative
EP1404329A4 (fr) * 2001-06-04 2006-11-02 Cytovia Inc Quinolinones 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1h)- substituees, et analogues utilises comme activateurs de caspases et inducteurs d'apoptose, et utilisation relative
KR20030066927A (ko) * 2002-02-06 2003-08-14 구자영 쿠르쿠민과 5-프루오로유라실로 이루어진 항암제 및 이항암제의 용도
CN102180849A (zh) * 2011-03-24 2011-09-14 广东工业大学 一种二芳基二烯环酮衍生物及其制备方法与应用
CN102293770A (zh) * 2011-05-25 2011-12-28 温州医学院 新型成纤维细胞生长因子受体酪氨酸激酶抑制剂
WO2018049296A1 (fr) * 2016-09-12 2018-03-15 Padlock Therapeutics, Inc. Inhibiteurs hétéroaryles de pad4
US11026937B2 (en) 2016-09-12 2021-06-08 Padlock Therapeutics, Inc. Heteroaryl inhibitors of PAD4
CN113908146A (zh) * 2021-07-16 2022-01-11 温州医科大学附属第一医院 5-溴刺甘草查尔酮化合物在制备抗癌药物中的应用
CN113908146B (zh) * 2021-07-16 2024-04-02 温州医科大学附属第一医院 5-溴刺甘草查尔酮化合物在制备抗癌药物中的应用

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