Design, synthesis and activity evaluation of quinolinone derivatives as EZH2 inhibitors

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2^WT IC₅₀ = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2^WT IC₅₀ = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.