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 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.