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

Alessandra Cipriano, Ciro Milite, Alessandra Feoli, Monica Viviano, Giacomo Pepe, Pietro Campiglia, Giuliana Sarno, Sarah Picaud, Satomi Imaide, Nikolai Makukhin, Panagis Filippakopoulos, Alessio Ciulli, Sabrina Castellano (Lead / Corresponding author), Gianluca Sbardella

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Abstract

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 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

Original languageEnglish
Article numbere202200343
Number of pages14
JournalChemMedChem
Volume17
Issue number20
Early online date30 Aug 2022
DOIs
Publication statusPublished - 19 Oct 2022

Keywords

  • Benzimidazole-6-sulfonamide
  • Bromodomain
  • Bioisosteres
  • Selectivity
  • Structure-activity relationships

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