Pharmacological inhibition of KDM5A for cancer treatment

Guan-Jun Yang; Jia Wu; Liang Miao; Ming-Hui Zhu; Qian-Jin Zhou; Xin-Jiang Lu; Jian-Fei Lu; Chung-Hang Leung; Dik-Lung Ma; Jiong Chen

doi:10.1016/j.ejmech.2021.113855

Pharmacological inhibition of KDM5A for cancer treatment

Eur J Med Chem. 2021 Dec 15:226:113855. doi: 10.1016/j.ejmech.2021.113855. Epub 2021 Sep 15.

Authors

Affiliations

¹ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, Zhejiang, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, 999078, China.
³ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, 999078, China. Electronic address: duncanleung@um.edu.mo.
⁴ Department of Chemistry, Hong Kong Baptist University, Kowloon, Hong Kong, 999077, China. Electronic address: edmondma@hkbu.edu.hk.
⁵ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, Zhejiang, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo, 315211, China. Electronic address: jchen1975@163.com.

PMID: 34555614
DOI: 10.1016/j.ejmech.2021.113855

Abstract

Lysine-specific demethylase 5A (KDM5A, also named RBP2 or JARID1A) is a demethylase that can remove methyl groups from histones H3K4me1/2/3. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, drug resistance, and is associated with poor prognosis. Pharmacological inhibition of KDM5A has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of KDM5A, its role in carcinogenesis, a comparison of currently available approaches for screening KDM5A inhibitors, a classification of KDM5A inhibitors, and its potential as a drug target in cancer therapy.

Keywords: Cancer therapy; Drug resistance; Histone methylation; Lysine-specific demethylase 5A; Screening methods.

Publication types

Review

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / metabolism
Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
Retinoblastoma-Binding Protein 2 / chemistry
Retinoblastoma-Binding Protein 2 / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
KDM5A protein, human
Retinoblastoma-Binding Protein 2