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 ( K D <1.0 µM). PQB‐4 exhibited marked antiproliferative activity against pancreatic cancer cell lines, including MIA PaCa‐2 (IC 50 = 2.9 µM), PANC‐1 (IC 50 = 4.5 µM), and gemcitabine‐resistant PANC‐1 cells (IC 50 = 5.0 µM), while showing substantially lower toxicity toward noncancerous HK‐2 cells (IC 50 = 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.