RESUMO
The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
Assuntos
Antineoplásicos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Pirróis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Masculino , Camundongos , Modelos Moleculares , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.