Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present)

Xingrui He; Hang Zhang; Yingqian Zhang; Yang Ye; Shuo Wang; Renren Bai; Tian Xie; Xiang-Yang Ye

doi:10.1016/j.ejmech.2022.114143

Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present)

Eur J Med Chem. 2022 Mar 5:231:114143. doi: 10.1016/j.ejmech.2022.114143. Epub 2022 Jan 20.

Authors

Xingrui He¹, Hang Zhang², Yingqian Zhang¹, Yang Ye¹, Shuo Wang³, Renren Bai⁴, Tian Xie⁵, Xiang-Yang Ye⁶

Affiliations

¹ School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
² School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
³ School of Pharmacy, Liaocheng University, Shandong, 252000, China.
⁴ School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. Electronic address: renrenbai@hznu.edu.cn.
⁵ School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. Electronic address: xbs@hznu.edu.cn.
⁶ School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. Electronic address: xyye@hznu.edu.cn.

PMID: 35101649
DOI: 10.1016/j.ejmech.2022.114143

Abstract

Post-translational modifications (PTMs) of histone by histone demethylases (KDMs) play an important role in the regulation of gene expression, which implicates the development of various human cancers and other diseases. Discovering and developing inhibitors targeting KDMs have become an active and fast-growing research area over the past decades. In this review, the latest emerging small-molecule inhibitors of KDMs were surveyed with the emphasis on the literature since 2018, including lysine specific demethylases (LSD or KDM1) inhibitors and JmjC family N-methyl lysine demethylases (JmjC KDMs, i.e. KDM2-7) inhibitors. The drug design strategy, the structure-activity relationships (SARs), the analysis and insight of co-crystal structures, and the mechanisms of action (MOA) were also discussed.

Keywords: Cancer therapy; Epigenetics; Histone lysine demethylases (KDMs); Inhibitor.

Publication types

Review

MeSH terms

Drug Discovery*
Histone Demethylases*
Histones / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases
Lysine / metabolism
Structure-Activity Relationship

Substances

Histones
Histone Demethylases
Jumonji Domain-Containing Histone Demethylases
Lysine