Discovery of Benzo[d]imidazole‐6‐sulfonamides as Bromodomain and Extra‐Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

The bromodomain and extra‐terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis‐specific protein, BRDT, each containing two N‐terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological rol...

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Detalles Bibliográficos
Autores principales: Cipriano, Alessandra, Milite, Ciro, Feoli, Alessandra, Viviano, Monica, Pepe, Giacomo, Campiglia, Pietro, Sarno, Giuliana, Picaud, Sarah, Imaide, Satomi, Makukhin, Nikolai, Filippakopoulos, Panagis, Ciulli, Alessio, Castellano, Sabrina, Sbardella, Gianluca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Research Articles
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9826262/
https://www.ncbi.nlm.nih.gov/pubmed/36040095
http://dx.doi.org/10.1002/cmdc.202200343
Descripción
Sumario:The bromodomain and extra‐terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis‐specific protein, BRDT, each containing two N‐terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole‐6‐sulfonamides starting from the azobenzene compounds MS436 (7 a) and MS611 (7 b) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most‐promising compound (9 a) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

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