Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain

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 immunoinflammat...

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Published inJournal of medicinal chemistry Vol. 61; no. 10; pp. 4317 - 4334
Main Authors Law, Robert P, Atkinson, Stephen J, Bamborough, Paul, Chung, Chun-wa, Demont, Emmanuel H, Gordon, Laurie J, Lindon, Matthew, Prinjha, Rab K, Watson, Allan J. B, Hirst, David J
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 24.05.2018
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
MEDICINAL CHEMISTRY
POTENT
PROTEIN
SMALL-MOLECULE INHIBITORS
INFLAMMATION
DRUG DISCOVERY
HOLE APPROACH
P-TEFB
FAMILY
BRD4
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Summary: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.
Bibliography:ObjectType-Article-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01666