Design, synthesis and biological evaluation of EZH2/HDAC dual inhibitors for the treatment of lymphomas

As the most common hematologic malignancy, lymphoma poses a significant threat to human health and contributes substantially to the global Cancer burden. It has been reported that the combination of EZH2 and HDAC inhibitors may be a promising strategy to enhance their Anticancer efficacy and even treat tumors being insensitive to EZH2 inhibitors. In our current work, two series of EZH2/HDAC dual inhibitors were designed and synthesized, where YM1240 was discovered as the most potent compound by the SAR studies. Compound YM1240 exhibited superior anti-proliferative effects compared to combination therapy across multiple lymphoma cell lines. Further mechanism studies showed that YM1240 inhibited cell proliferation and induced Apoptosis and cell cycle arrest. Moreover, YM1240 exhibited in vivo antitumor efficacy in lymphoma xenograft models, in which both EZH2 and HDAC pathways were sufficiently inhibited as indicated by decreased H3K27me3 and increased H3K9ac and H4ac in immunohistochemical stained tumor tissues. Therefore, YM1240 was a potential EZH2/HDAC dual inhibitor that may pave a new approach for treating lymphomas.