Antitumor activity of small molecule ligands targeting hTERT promoter G4

• 1、School of biomedical and pharmaceutical sciences, Guangdong University of Technology

Abstract：Telomerase represents a pivotal therapeutic target in oncology, garnering widespread interest for the development of telomerase inhibitors. The G-quadruplex (G4) structure emerges as an innovative nucleic acid motif with regulatory implications in tumor biology, holding promise as a novel therapeutic target for cancer treatment. This research delves into the advancement of ligands that specifically bind to the hTERT gene\'s promoter G-quadruplex (hTERT-G4), thereby inhibiting hTERT gene expression and exerting anti-tumor effects.In this investigation, we identified a hTERT-G4 binding ligand, 4e, from a benzothiazole-based compound library previously established by our team. We employed a suite of biophysical techniques to elucidate the interaction mechanism between 4e and hTERT-G4. Furthermore, we assessed the antitumor potency of 4e using cancer cell lines exhibiting varying levels ofhTERT expression.Our findings reveal that 4e effectively interacts with and stabilizes the hTERT-G4 conformation, thereby inducing cytotoxicity and impeding the proliferation of a range of tumor cells. Notably, the cytotoxic effect of 4e was positively correlated with the level of hTERT expression in the cells. This correlation suggests that 4e mediates its anti-tumor activity by modulating hTERT expression through its interaction with the hTERT-G4 structure.This study paves the way for innovative approaches in the development of new hTERT inhibitors, potentially offering a fresh perspective in the quest for effective cancer therapeutics.

Keywords： Antitumor G-quadruplex Telomerase reverse transcriptase Telomerase Benzothiazole derivatives