RESUMEN
The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.
Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , Isoxazoles/farmacología , Mieloma Múltiple/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Administración Oral , Animales , Bencimidazoles/química , Bencimidazoles/metabolismo , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Isoxazoles/administración & dosificación , Isoxazoles/química , Isoxazoles/metabolismo , Ratones , Estructura Molecular , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Dominios Proteicos/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
