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1.
Eur J Med Chem ; 220: 113534, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34038857

RESUMO

Inhibition of MER receptor tyrosine kinase (MERTK) causes direct tumor cell killing and stimulation of the innate immune response. Therefore, MERTK has been identified as a therapeutic target in a wide variety of human tumors. Clinical trials targeting MERTK have recently been initiated, however, none of these drugs are MERTK-specific. Herein, we present the discovery of a highly MERTK-selective inhibitor UNC5293 (24). UNC5293 has subnanomolar activity against MERTK with an excellent Ambit selectivity score (S50 (100 nM) = 0.041). It mediated potent and selective inhibition of MERTK in cell-based assays. Furthermore, it has excellent mouse PK properties (7.8 h half-life and 58% oral bioavailability) and was active in bone marrow leukemia cells in a murine model.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , c-Mer Tirosina Quinase/antagonistas & inibidores , Administração Oral , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , c-Mer Tirosina Quinase/metabolismo
2.
J Med Chem ; 61(22): 10242-10254, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30347155

RESUMO

Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , c-Mer Tirosina Quinase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Metilação , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Distribuição Tecidual , c-Mer Tirosina Quinase/química , c-Mer Tirosina Quinase/metabolismo
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