Structure based discovery of novel hexokinase 2 inhibitors

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 excellent 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.