RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Piperazinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirroles/síntesis química , Adenosina Trifosfato/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasas , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Pirroles/química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
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.
