RESUMEN
This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Artritis Experimental/tratamiento farmacológico , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/farmacología , Animales , Colágeno/toxicidad , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/química , Humanos , RatasRESUMEN
The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.
Asunto(s)
Indolizinas/síntesis química , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Células HT29 , Humanos , Indolizinas/administración & dosificación , Indolizinas/uso terapéutico , Quinasas Quinasa Quinasa PAM/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/administración & dosificación , Pirroles/uso terapéutico , Ratas , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.