RESUMO
Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.
Assuntos
Aminopeptidases/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glicoproteínas/antagonistas & inibidores , Indazóis/farmacologia , Obesidade/tratamento farmacológico , Administração Oral , Aminopeptidases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Glicoproteínas/metabolismo , Humanos , Indazóis/síntese química , Indazóis/química , Metionil Aminopeptidases , Camundongos , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirrolidinonas/farmacologia , Quinase Syk/antagonistas & inibidores , Animais , Antineoplásicos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirrolidinonas/administração & dosagem , Pirrolidinonas/química , Relação Estrutura-Atividade , Quinase Syk/metabolismoRESUMO
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
Assuntos
Desenho de Fármacos , Receptores de Vitronectina , Animais , Ratos , Humanos , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Relação Estrutura-Atividade , Cirrose Hepática/tratamento farmacológico , Modelos Moleculares , Descoberta de Drogas , Ratos Sprague-Dawley , Masculino , Cristalografia por Raios X , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese químicaRESUMO
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Desenho de Fármacos , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/farmacologia , Piridonas/farmacologia , Animais , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/química , Teste de Tolerância a Glucose , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Piridonas/administração & dosagem , Piridonas/química , Relação Estrutura-AtividadeRESUMO
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
RESUMO
Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.