RESUMO
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/química , Aurora Quinase A/metabolismo , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/química , Aurora Quinase B/metabolismo , Aurora Quinase C/antagonistas & inibidores , Aurora Quinase C/química , Aurora Quinase C/metabolismo , Aurora Quinases/química , Aurora Quinases/metabolismo , Benzimidazóis/química , Benzimidazóis/metabolismo , Feminino , Células HCT116 , Humanos , Camundongos SCID , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolonas/química , Quinolonas/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.
