Design, synthesis and antiproliferative activity of pyridone derivatives as potent enhancer of zeste homologue 2/histone deacetylase dual inhibitors

Abstract

The development of dual inhibitors of histone deacetylases (HDACs) and enhancer of zeste homologue 2 (EZH2) is an efficient strategy that not only synergistically suppresses critical pathways in tumorigenesis but also circumvents the potential risks of drug cocktails. In this study, a series of pyridone derivatives were rationally designed via pharmacophore merging, and N1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N8-hydroxyoctanediamide (15c) was identified as the most potent compound against hematological tumor cells MV4-11 and SU-DHL-10, with IC50 values in the submicromolar range. 15c also effectively inhibited HDAC1 and EZH2 with IC50 values of 9.2 nM and 311.1 nM, respectively. Molecular simulations revealed key interactions between 15c and both targets. These findings indicated that compound 15c warrants further investigation as a novel dual HDAC/EZH2 agent.