Discovery of YSR734: A Covalent HDAC Inhibitor with Cellular Activity in Acute Myeloid Leukemia and Duchenne Muscular Dystrophy

Histone deacetylases (HDACs) have emerged as powerful
epigenetic
modifiers of histone/non-histone proteins via catalyzing the deacetylation
of ε-N-acetyl lysines. The dysregulated activity
of these Zn2+-dependent hydrolases has been broadly implicated
in disease, notably cancer. Clinically, the recurring dose-limiting
toxicities of first-generation HDACi sparked a paradigm shift toward
safer isoform-specific molecules. With pervasive roles in aggressive
diseases, there remains a need for novel approaches to target these
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 preclinical covalent HDACi.