YX226

YX226 is a second-generation, first-in-class dual histone deacetylase 3 (HDAC3) and histone deacetylase 8 (HDAC8) proteolysis-targeting chimera (PROTAC) degrader. Developed to overcome the poor metabolic stability of its predecessor, YX968, YX226 maintains potent degradation activity and selectivity for HDAC3 and HDAC8 over other HDAC isoforms. In preclinical models of diffuse large B-cell lymphoma (DLBCL), particularly the activated B-cell-like (ABC) subtype, YX226 induces caspase-3-mediated apoptosis and cell cycle arrest. Mechanistically, it upregulates H3K27 acetylation and enhances the expression of antigen presentation markers MHC-I and MHC-II, thereby promoting CD8+ T-cell-induced cytotoxicity. YX226 has demonstrated significant in vivo tumor growth inhibition and protein degradation in xenograft models without adverse effects on body weight.