Exploration of chromenone-based ligands as DNA G-quadruplex targets in triple-negative breast cancer

Triple-negative breast Cancer (TNBC) is a highly aggressive and metastatic subtype of breast Cancer with limited treatment options and poor prognosis. Therefore, there is a pressing need for novel anti-cancer treatments for TNBC. G-quadruplexes (G4s), secondary nucleic acid structures, play essential biological roles in regulating the expression of oncogenes. With the discovery of G4 structures in oncogenes related to breast Cancer, G4 ligands have gained interest as promising candidates for TNBC treatment. This study aimed to investigate the potential of chromenone derivatives as G4 ligands with novel pharmacophores and to evaluate their in vitro anti-TNBC activity. In this study, three series of chromenone derivatives with various amine substitutions at different positions were synthesized and tested against TNBC cells. Among them, compound 17, bearing two N-methyl piperazine moieties, exhibited notable cytotoxicity towards TNBC cell lines. Mechanistic investigation revealed that it downregulated hTERT expression, thereby likely exerting an anti-cancer effect by binding and stabilizing the hTERT G4, with high selectivity and affinity for parallel G4 structures. In line with this, compound 17 was found to inhibit the non-canonical functions of hTERT, leading to S/G2 cell cycle arrest and Apoptosis. This study offers insights into the potential application of chromenone as a novel pharmacophore for G4-stabilizing ligands in the development of anti-TNBC therapeutics.

Anticancer; G-quadruplex; G-quadruplex ligand; hTERT, Chromenone, TNBC.