Structure based discovery of novel hexokinase 2 inhibitors
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Updated: Dec 29, 2025
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Yang Liu1, Mingxue Li1, Yujie Zhang1
1Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
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.
Insights
Researchers identified novel compounds targeting Hexokinase 2 (HK2), an enzyme overexpressed in many cancers. Compound 3j demonstrated potent inhibition of HK2 and cancer cell growth, showing promise for new cancer therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Hexokinase 2 (HK2) is frequently overexpressed in human cancers.
- HK2 plays a crucial role in cancer cell metabolism and proliferation.
- HK2 is recognized as a promising therapeutic target for cancer treatment.
Purpose of the Study:
- To identify novel inhibitors of Hexokinase 2 (HK2).
- To design, synthesize, and evaluate arylhydrazide derivatives for HK2 inhibitory activity.
- To assess the efficacy of synthesized compounds against cancer cell lines.
Main Methods:
- Structure-based virtual screening of over 6 million compounds to identify lead structures.
- Synthesis of 26 (E)-N'-(2,3,4-trihydroxybenzylidene) arylhydrazide derivatives.
- In vitro evaluation of enzyme activity and IC50 values against HK2 and cancer cell lines (SW480).
Main Results:
- Most of the 26 synthesized compounds exhibited excellent in vitro activity.
- Compound 3j displayed the most potent inhibition of HK2 enzyme activity (IC50 = 0.53 ± 0.13 μM).
- Compound 3j demonstrated significant growth inhibition against SW480 cancer cells (IC50 = 7.13 ± 1.12 μM).
Conclusions:
- The designed arylhydrazide derivatives show significant potential as HK2 inhibitors.
- Compound 3j is a promising lead candidate for further development in cancer therapy.
- Targeting HK2 with novel inhibitors represents a viable strategy for cancer treatment.
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