Computational discovery and biological evaluation of novel inhibitors targeting histone-lysine N-methyltransferase SET7

Wenjian Min; Zeng Hou; Fang Zhang; Shengnan Xie; Kai Yuan; Haojie Dong; Liping Wang; Lianwen Qi; Cheng Luo; Hong Ding; Peng Yang

doi:10.1016/j.bmc.2020.115372

Computational discovery and biological evaluation of novel inhibitors targeting histone-lysine N-methyltransferase SET7

Bioorg Med Chem. 2020 Apr 1;28(7):115372. doi: 10.1016/j.bmc.2020.115372. Epub 2020 Feb 13.

Authors

Wenjian Min¹, Zeng Hou², Fang Zhang¹, Shengnan Xie¹, Kai Yuan¹, Haojie Dong¹, Liping Wang¹, Lianwen Qi³, Cheng Luo², Hong Ding⁴, Peng Yang⁵

Affiliations

¹ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
⁴ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].
⁵ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].

PMID: 32088124
DOI: 10.1016/j.bmc.2020.115372

Abstract

Histone-lysine N-methyltransferase SET7 emerged as a potential target for multiple cancers. In a virtual screening program used to explore new and potent inhibitors of SET7, compound 16 was discovered as a top hit with an IC₅₀ value of 6.02 μM. A further similarity search afforded a new compound 23, which exhibited better activity against SET7 with an IC₅₀ value of 1.96 μM. Importantly, compound 23 selectively inhibited the proliferation of MV4-11 cells. Comprehensively, compound 23 can serve as a lead for further identification and development of more potent SET7 inhibitors.

Keywords: Histone methylation; Lysine methyltransferase; SET7; Small-molecule inhibitor; Virtual screening.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Catalytic Domain
Cell Line, Tumor
Cell Survival / drug effects
Computational Chemistry
Computer Simulation
Drug Discovery*
Escherichia coli / metabolism
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Molecular Structure
Protein Binding
Protein Conformation
Structure-Activity Relationship

Substances

Antineoplastic Agents
Histone-Lysine N-Methyltransferase
SETD7 protein, human