Design, synthesis and biological evaluation of 4,6-diarylquinoxaline-based KDM4D inhibitors

[Display omitted] •Design and synthesis of a series of 4,6-diarylquinoxaline-based KDM4D inhibitors.•The promising compound 33a has an IC50 of 0.62 μM against KDM4D.•Structure-activity relationship was elucidated through molecular docking and 3D pharmacophore studies.•Compound 33a presents notable anti-cancer activity in liver cancer cells. Histone lysine demethylase 4D (KDM4D) is a critical player in the regulation of tumorigenesis, emerging as a potential target for developing anti-tumor agents. In this study, a series of KDM4D inhibitors containing the 4,6-diarylquinoxaline scaffold were prepared based on the previously discovered hit compound QD-1. Among these inhibitors, 33a was the most potent compound, with an IC50 value of 0.62 μM. In an in vitro assay, 33a showed a superior ability to inhibit the viability of liver cancer Huh-7 cells with IC50 = 5.23 μM. 33a exhibits significant effects in inhibiting cell cycle progression and proliferation of liver cancer cells, as well as suppressing cell migration. This work provided a promising scaffold for developing KDM4D inhibitors, as well as a lead compound for the development of anti-tumor drugs targeting KDM4D.