RESUMO
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Assuntos
Antineoplásicos/síntese química , Benzazepinas/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Lactamas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tionas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactamas/farmacocinética , Lactamas/farmacologia , Camundongos , Camundongos Nus , Mitose , Modelos Moleculares , Transplante de Neoplasias , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tionas/farmacocinética , Tionas/farmacologia , Transplante Heterólogo , Quinase 1 Polo-LikeRESUMO
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
