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

• DOI: 10.1002/cmdc.202200343
• Publication Date: 2022-08-30T12:12:23Z
• Authors: Alessandra Cipriano; Ciro Milite; Alessandra Feoli; Monica Viviano; Giacomo Pepe; Pietro Campiglia; Giuliana Sarno; Sarah Picaud; Satomi Imaide; Nikolai Makukhin; Panagis Filippako...; Alessio Ciulli; Sabrina Castellano; Gianluca Sbardella
• Keywords: Male; 0301 basic medicine; Sulfonamides; Bioisosteres; Imidazoles; Bromodomain; 610; Nuclear Proteins; Structure-activity relationships; Cell Cycle Proteins; 540; Benzimidazole-6-sulfonamide; Benzimidazole-6-sulfonamide; Bioisosteres; Bromodomain; Selectivity; Structure-activity relationships; 03 medical and health sciences; Benzo(a)pyrene; Humans; Selectivity; Benzimidazoles; Research Articles; Transcription Factors

AbstractThe 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.