EPZ-719

EPZ-719 is a potent and selective small molecule inhibitor of SET domain containing 2 (SETD2), a histone H3 lysine 36 (H3K36) methyltransferase. SETD2 is the primary enzyme responsible for the trimethylation of H3K36 (H3K36me3), an epigenetic modification associated with transcriptional elongation, DNA repair, and RNA splicing. By inhibiting SETD2, EPZ-719 reduces global H3K36me3 levels, which has been shown to induce cell cycle arrest and apoptosis in specific cancer models. Preclinical research has identified SETD2 as a critical dependency in multiple myeloma, particularly in cell lines resistant to immunomodulatory drugs (IMiDs) like lenalidomide and cereblon E3 ligase modulators (CELMoDs) like iberdomide. The compound was developed by Epizyme (now part of Ipsen) as part of their epigenetic modulator pipeline.