RESUMO
Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.
Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Piperazinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/síntese química , Trifosfato de Adenosina/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
We describe the synthesis of a series of low molecular weight inhibitors of the alphavbeta3 integrin obtained by modifying a high-throughput screening hit with micromolar activity. A solid phase synthesis to prepare 3-phenylthio-3-nicotinyl propionic acid derivatives, exemplified by 13c, was set up. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit cell adhesion mediated by vitronectin have been obtained.