RESUMO
Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.
Assuntos
Acetamidas/síntese química , Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Ciclina A/antagonistas & inibidores , Pirazóis/síntese química , Acetamidas/química , Acetamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Quinases relacionadas a CDC2 e CDC28/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclina A/química , Quinase 2 Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Transplante de Neoplasias , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Two-dimensional libraries of 4-acylamino-1,3-thiazoles 9 were prepared via Curtius rearrangement of 1,3-thiazole-4-carbonyl azides 6, trapping of the intermediate isocyanates with oxime resin, and thermal regeneration of the isocyanates from the washed resin in the presence of nucleophiles. Several compounds proved to be selective inhibitors of CDK5/p25 versus the closely homologous CDK2/cyclin A enzyme, with the best analogue (43) possessing over 100-fold selectivity.
