JYQ-42

JYQ-42 is a potent and selective small molecule allosteric inhibitor of Sirtuin 6 (SIRT6), a member of the NAD+-dependent deacetylase superfamily. Identified through a reversed allosteric strategy (AlloReverse), JYQ-42 targets a cryptic allosteric site designated as Pocket Z, which is induced by the binding of NAD+ to the orthosteric site. The compound exhibits an IC50 of 2.33 μmol/L and demonstrates high selectivity for SIRT6 over other histone deacetylases (HDACs). Preclinical research indicates that JYQ-42 effectively suppresses SIRT6-mediated cancer cell migration and the production of pro-inflammatory cytokines, highlighting its potential as a therapeutic lead for oncology and inflammatory disorders.