RESUMEN
Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
Asunto(s)
Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazoles/síntesis química , Piridinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Crizotinib , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Modelos Moleculares , Conformación Molecular , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of quinoline-containing c-Met inhibitors were prepared and studied. Chemistry was developed to introduce a pyridyl moiety onto the 2-aryl ring present in a lead molecule which mitigated the potential for quinone formation relative to the original compound. The study also assessed the importance of an acylthiourea moiety present in the lead structure for effective binding to the c-Met protein ATP site.