RESUMO
The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.
Assuntos
Desenho de Fármacos , Isoquinolinas/química , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Simulação de Dinâmica Molecular , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Cristalografia por Raios X , Estrutura Molecular , c-Mer Tirosina Quinase , Receptor Tirosina Quinase AxlRESUMO
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.
Assuntos
Antivirais/síntese química , Ácidos Borônicos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Indazóis , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Indazóis/farmacologia , Indazóis/farmacocinética , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Sulfonas/farmacologia , Sulfonas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Linhagem Celular Tumoral , Sistema Livre de Células , Córnea/patologia , Relação Dose-Resposta a Droga , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonas/administração & dosagem , Sulfonas/sangue , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
An efficient and regioselective synthesis of 2-methyl-2H-indazoles and 2-ethyl-2H-indazoles using trimethyloxonium tetrafluoroborate or triethyloxonium hexafluorophosphate is reported.