Hexokinase 2 inhibition study of lonidamine-tacrine/quinazoline hybrids: Design, synthesis, molecular docking, and dynamics simulations

Glycolysis inhibition is known as a therapeutic method for cancer therapy. Hexokinase 2 (HK2) is the rate-limiting enzyme, catalyzing the critical process of glucose phosphorylation for later use in glycolysis and other signaling pathways. Positive HK2 expression often supports cancer cell survival while systemic deletion or inhibition of HK2 has shown to hinder tumor growth. Herein, we have employed a structure-based approach, designed and synthesized conjugates of Lonidamine (LND), a known HK2 inhibitor, and evaluated their HK2 enzyme inhibitory activity. In particular, the LND-tacrine and LND-quinazoline conjugates connected through amide linkages of different linker lengths have been explored as potent HK2 inhibitors in vitro. The hit molecules have been identified in the study that inhibit HK2 at sub-micromolar concentrations working better than the parent LND molecule. These molecules have shown selective cytotoxicity against cancerous HepG2 cells than the non-malignant HEK cells. Additionally, some of these conjugates have acted as PROTACs/degraders that have shown dose dependent, systematic degradation of HK2 in HepG2 cells. Hence, for the first time tacrine and quinazoline motifs have been explored as degraders. These findings have been backed by docking and simulation study.