Discovery of Benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain.
Benzimidazole-6-sulfonamide
Bioisosteres
Bromodomain
Selectivity
Structure-activity relationships
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
19 10 2022
19 10 2022
Historique:
revised:
29
08
2022
received:
27
06
2022
pubmed:
31
8
2022
medline:
22
10
2022
entrez:
30
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36040095
doi: 10.1002/cmdc.202200343
pmc: PMC9826262
doi:
Substances chimiques
Sulfonamides
0
Nuclear Proteins
0
Benzo(a)pyrene
3417WMA06D
Transcription Factors
0
Imidazoles
0
Benzimidazoles
0
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202200343Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/J001201/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100476/Z/12/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 094090/Z/10/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 095751/Z/11/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N010051/1
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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