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

Zhen Fang; Yang Liu; Rong Zhang; Qiang Chen; Tianqi Wang; Wei Yang; Yan Fan; Chundong Yu; Rong Xiang; Shengyong Yang

doi:10.1016/j.ejmech.2021.113662

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

Eur J Med Chem. 2021 Nov 5:223:113662. doi: 10.1016/j.ejmech.2021.113662. Epub 2021 Jun 26.

Authors

Zhen Fang¹, Yang Liu², Rong Zhang², Qiang Chen³, Tianqi Wang⁴, Wei Yang², Yan Fan⁴, Chundong Yu⁵, Rong Xiang⁶, Shengyong Yang⁷

Affiliations

¹ Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041, China.
³ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, 361102, China.
⁴ Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, China.
⁵ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, 361102, China. Electronic address: cdyu@xmu.edu.cn.
⁶ Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, China. Electronic address: rxiang@nankai.edu.cn.
⁷ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041, China. Electronic address: yangsy@scu.edu.cn.

PMID: 34237635
DOI: 10.1016/j.ejmech.2021.113662

Abstract

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 μM. 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.

Keywords: 2-OG noncompetitive Inhibitor; Epigenetics; KDM4D; Structure-activity relationship.

MeSH terms

Binding Sites
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
Jumonji Domain-Containing Histone Demethylases / metabolism
Ketoglutaric Acids / chemistry
Ketoglutaric Acids / metabolism
Molecular Dynamics Simulation
Phenols / chemistry
Phenols / metabolism
Phenols / pharmacology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Ketoglutaric Acids
Phenols
Jumonji Domain-Containing Histone Demethylases
KDM4D protein, human
KDM4A protein, human