Discovery of JMJD7 inhibitors with the aid of virtual screening and bioactivity evaluation

Wenqing Zhang; Kan Li; Tianqi Wang; Ming Wu; Linli Li

doi:10.1016/j.bmcl.2021.128139

Discovery of JMJD7 inhibitors with the aid of virtual screening and bioactivity evaluation

Bioorg Med Chem Lett. 2021 Aug 1:45:128139. doi: 10.1016/j.bmcl.2021.128139. Epub 2021 May 25.

Authors

Wenqing Zhang¹, Kan Li², Tianqi Wang², Ming Wu², Linli Li³

Affiliations

¹ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, China.
³ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: lilinli@scu.edu.cn.

PMID: 34048880
DOI: 10.1016/j.bmcl.2021.128139

Abstract

Jumonji-C (JmjC) domain-containing 7 (JMJD7), which is a 2-oxoglutarate (2OG)-dependent oxygenase, has been demonstrated to play an important role in the occurrence and development of a number of diseases, particularly cancer. Discovery of JMJD7 inhibitors is thus of great importance. Herein consensus docking/scoring strategy and bioactivity evaluation were used to identify JMJD7 inhibitors from various chemical databases. Seven active compounds were retrieved. The most potent compound, Cpd-3, showed an IC₅₀ value of 6.62 μM against JMJD7. Further biophysical assays confirmed that Cpd-3 could efficiently bind to JMJD7 in vitro. Flexible docking was used to predict the binding mode of Cpd-3 with JMJD7. In a cellular assay, Cpd-3 displayed good inhibitory activity against cancer cell lines expressing a high level of JMJD7. As far as we know, Cpd-3 is the first JMJD7 inhibitor reported so far. Overall, this study established a good starting point for drug discovery targeting JMJD7.

Keywords: Consensus docking; Epigenetics; JMJD7; Small molecule inhibitor; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Chlorobenzoates / chemical synthesis
Chlorobenzoates / chemistry
Chlorobenzoates / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
Jumonji Domain-Containing Histone Demethylases / metabolism
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Chlorobenzoates
Enzyme Inhibitors
2,4-dichlorobenzoic acid
Jumonji Domain-Containing Histone Demethylases