Discovery of a potent and selective inhibitor of histone lysine demethylase KDM4D

Histone lysine demethylase 4D (KDM4D) plays an important role in the regulation of tumorigenesis, progression and drug resistance and has been considered a potential target for cancer treatment. However, there is still a lack of potent and selective KDM4D inhibitors. In this investigation, we report a new class of KDM4D inhibitors containing the 2-(aryl(pyrrolidine-1-yl)methyl)phenol scaffold, identified through AlphaLisa-based screening, structural optimization, and structure-activity relationship analyses. Among these inhibitors, 24s was the most potent, with an IC50 value of 0.023 +/- 0.004 mu M. This compound exhibited more than 1500-fold selectivity towards KDM4D versus KDM4A as well as other JMJD subfamily members, indicating good selectivity for KDM4D. Kinetic analysis indicated that 24s did not occupy the 2-oxoglutarate binding pocket. In an in vitro assay, 24s significantly suppressed the proliferation and migration of colorectal cancer (CRC) cells. Overall, this study has identified a good tool compound to explore the biological function of KDM4D and a good lead compound for drug discovery targeting KDM4D. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A new class of KDM4D inhibitors, with 24s being the most potent, has been identified with good selectivity. These inhibitors showed significant suppression in in vitro assays, serving as promising lead compounds for drug discovery targeting KDM4D.