Design, synthesis and evaluation of styrylquinolinium derivatives targeting c-MYC /BCL2 G-quadruplexes against breast cancer

The G-quadruplex (G4) structures in the promoter regions of proto-oncogenes c-Myc and BCL2, which suppress transcription, have emerged as potential therapeutic targets for breast Cancer. This study proposes a dual-targeting G4 ligand design strategy to synergistically block their oncogenic functions through simultaneous stabilization of c-Myc and BCL2 G4 structures.Based on the topological features of c-Myc and BCL2G4, fifteen styrylquinoline derivatives were designed and synthesized. Among them, compound Z4 exhibited dual-target binding affinities, potent antiproliferative activity against breast Cancer cells, and a binding preference for specific G4 subtypes. The interaction mechanisms of compound Z4 with both G4s were characterized using electrospray ionization mass spectrometry (ESI-MS), fluorescence spectroscopy, UV-vis spectroscopy, and circular dichroism (CD) spectroscopy, with molecular docking and molecular dynamics (MD) simulations further elucidating atomistic binding features. In vitro, Z4 inhibits c-Myc and BCL2 gene transcription by binding to G4-forming sequences and downregulates their protein expression. Cellular assays demonstrated that Z4 suppresses tumor cell migration, induces caspase-dependent Apoptosis, and triggers cell cycle arrest.In vivo experiments demonstrated that Z4 significantly suppressed tumor growth in a 4T1 syngeneic model with no observable toxicity. Collectively, this study establishes a design strategy, successfully generating dual c-Myc/BCL2 targeting compound with potential for further development against breast Cancer.

BCL2; Breast cancer; C-MYC; Dual-target ligand; G-quadruplex.