Abstract:
:The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Law RP,Atkinson SJ,Bamborough P,Chung CW,Demont EH,Gordon LJ,Lindon M,Prinjha RK,Watson AJB,Hirst DJdoi
10.1021/acs.jmedchem.7b01666subject
Has Abstractpub_date
2018-05-24 00:00:00pages
4317-4334issue
10eissn
0022-2623issn
1520-4804journal_volume
61pub_type
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