Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain
| Autor: | 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, Gianluca Sbardella |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
Pharmacology Sulfonamides Bioisosteres Organic Chemistry Imidazoles Nuclear Proteins Bromodomain Cell Cycle Proteins Structure-activity relationships Biochemistry Benzimidazole-6-sulfonamide Selectivity Drug Discovery Benzo(a)pyrene Humans Molecular Medicine Benzimidazoles General Pharmacology Toxicology and Pharmaceutics Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|