YSR-734

Histone deacetylases (HDACs) have emerged as powerful epigenetic modifiers of histone/nonhistone proteins via catalyzing the deacetylation of ε-N-acetyllysines.The dysregulated activity of these Zn2+-dependent hydrolases has been broadly implicated in disease, notably cancer.Clin., the recurring dose-limiting toxicities of first generation HDACi sparked a paradigm shift toward safer isoform-specific mols.With pervasive roles in aggressive (and some cases orphan) diseases, there remains a need for novel approaches to target these unique enzymes.Herein, we report the discovery of YSR734, a first-in-class covalent HDACi, with a 2-aminobenzanilide Zn2+ chelate and a pentafluorobenzenesulfonamide electrophile.This class I selective proof-of-concept modified HDAC2Cys274 (catalytic domain), with nM potency against HDAC1-3, sub-μM activity in MV4-11 cells, and limited cytotoxicity in MRC-9 fibroblasts.In C2C12 myoblasts, YSR734 activated muscle-specific biomarkers myogenin/Cav3, causing potent differentiation into myotubes (applications in Duchenne Muscular Dystrophy).Current efforts are focused on improving in vivo ADME toward a preclin. covalent HDACi.