A DNA G-Quadruplex-Targeting Ligand Suppresses c-MYC Expression: Implications for Gemcitabine‑Resistant Pancreatic Cancer.

The MYC oncogene is dysregulated in nearly 70% of human cancers and plays a central role in tumor initiation and progression. However, direct targeting of c-MYC remains challenging because of its "undruggable" nature. Stabilization of DNA G-quadruplex (G4) structures within the c-MYC promoter offers an alternative strategy to suppress c-MYC transcription. Here, we report the synthesis and biological evaluation of a series of styryl quinolinium ligands, identifying PQB-4 as a selective c-MYC DNA G4-binder (KD <1.0 µM). PQB-4 exhibited marked antiproliferative activity against pancreatic cancer cell lines, including MIA PaCa-2 (IC50 = 2.9 µM), PANC-1 (IC50 = 4.5 µM), and gemcitabine-resistant PANC-1 cells (IC50 = 5.0 µM), while showing substantially lower toxicity toward noncancerous HK-2 cells (IC50 = 40.1 µM). Mechanistically, PQB-4 stabilized c-MYC DNA G4-structures, suppressed c-MYC mRNA and protein expression, induced G0/G1 cell-cycle arrest, and activated a p53-dependent DNA damage response. PQB-4 also promoted telomere damage, cellular senescence, mitochondrial dysfunction, ferroptosis, and mitophagy, while inhibiting cancer cell migration, proliferation, and survival. Notably, PQB-4 synergized strongly with gemcitabine in resistant PANC-1 cells (CI = 0.027). In a PANC-1 xenograft model, PQB-4 reduced tumor weight by 44%. These findings highlight c-MYC DNA G4 targeting by PQB-4 as a feasible therapeutic strategy for pancreatic cancer, particularly in gemcitabine-resistant disease.