Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode

Most
bromodomain inhibitors mimic the interactions of the natural
acetylated lysine (KAc) histone substrate through key interactions
with conserved asparagine and tyrosine residues within the binding
pocket. Herein we report the optimization of a series of phenyl sulfonamides
that exhibit a novel mode of binding to non-bromodomain and extra
terminal domain (non-BET) bromodomains through displacement of a normally
conserved network of four water molecules. Starting from an initial
hit molecule, we report its divergent optimization toward the ATPase
family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome
region, candidate 2 (CECR2) domains. This work concludes with the
identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2
inhibitor with excellent physicochemical properties.