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

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.