Structure based discovery of novel hexokinase 2 inhibitors

Yang Liu; Mingxue Li; Yujie Zhang; Canrong Wu; Kaiyin Yang; Suyu Gao; Mengzhu Zheng; Xingzhou Li; Hua Li; Lixia Chen

doi:10.1016/j.bioorg.2020.103609

Structure based discovery of novel hexokinase 2 inhibitors

Bioorg Chem. 2020 Mar:96:103609. doi: 10.1016/j.bioorg.2020.103609. Epub 2020 Jan 21.

Authors

Yang Liu¹, Mingxue Li¹, Yujie Zhang¹, Canrong Wu², Kaiyin Yang², Suyu Gao¹, Mengzhu Zheng³, Xingzhou Li⁴, Hua Li⁵, Lixia Chen⁶

Affiliations

¹ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
³ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: mengzhu_zheng@hust.edu.cn.
⁴ National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: xingzhouli@aliyun.com.
⁵ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: li_hua@hust.edu.cn.
⁶ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.

PMID: 32007722
DOI: 10.1016/j.bioorg.2020.103609

Abstract

Hexokinase 2 (HK2) is over-expressed in most of human cancers and has been proved to be a promising target for cancer therapy. In this study, based on the structure of HK2, we screened over 6 millions of compounds to obtain the lead. A total of 26 (E)-N'-(2,3,4-trihydroxybenzylidene) arylhydrazide derivatives were then designed, synthesized, and evaluated for their HK2 enzyme activity and IC₅₀ values against two cancer cell lines. Most of the 26 target compounds showed excellently in vitro activity. Among them, compound 3j showed the strongest inhibitory effects on HK2 enzyme activity with an IC₅₀ of 0.53 ± 0.13 μM and exhibited the most potent growth inhibition against SW480 cells with an IC₅₀ of 7.13 ± 1.12 μM, which deserves further studies.

Keywords: Cancer metabolism; Drug discovery; HK2 inhibitors; Structure-based virtual ligand screening.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Benzylidene Compounds / chemistry*
Benzylidene Compounds / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Design
Drug Discovery
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Hexokinase / antagonists & inhibitors*
Hexokinase / metabolism
Humans
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / enzymology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzylidene Compounds
Enzyme Inhibitors
HK2 protein, human
Hexokinase