Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy

[Display omitted] •A series of dual inhibitors targeting EZH2 and BRD4 have been designed, synthesized, and evaluated.•KWCX-28 exhibited BRD4 inhibitory activity and the activity of binding to EZH2.•KWCX-28 exhibited potent inhibitory activity against HCT-116 cells.•BRD4 related proteins were detected in EZH2Is GSK126-administered group. Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.