RESUMEN
Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).
Asunto(s)
Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Animales , Descubrimiento de Drogas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Dosis-Respuesta a Droga , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Ratas , Ensayos de Selección de Medicamentos Antitumorales , Evaluación Preclínica de MedicamentosRESUMEN
In the title compound, C(19)H(18)N(3) (+)·Br(-)·H(2)O, the dihedral angle between the allyl group and the imidazole ring is 89.59â (14)°, while the dihedral angle between the cyanophenyl ring and the imidazole ring is 78.72â (7)°. O-Hâ¯Br hydrogen bonds form an infinite chain in the c-axis direction and C-Hâ¯Br and C-Hâ¯O inter-actions expand this chain into an infinite three-dimensional network.
RESUMEN
In the title compound, C(19)H(18)N(3) (+)·Br(-), both the allyl and cyano-phenyl groups are approximately perpendicular to the central benzimidazole unit, making dihedral angles of 89.7â (2) and 85.09â (13)°, respectively. The crystal packing is dominated by C-Hâ¯Br inter-actions, with each anion inter-acting with five neighboring cations.