Non-fused imidazole-biphenyl analogs repress triple-negative breast cancer growth by mainly stabilizing the c-MYC...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Abnormal c-MYC oncogene expression drives triple-negative breast cancer (TNBC) pathogenesis.
• Stabilizing the c-MYC promoter G-quadruplex (G4) is a potential anti-TNBC strategy, but drug selectivity is a challenge due to numerous G4 sites.
• Developing selective ligands for c-MYC G4 is crucial for effective TNBC therapy.

Purpose of the Study:

• To design and synthesize novel small-molecule ligands with enhanced selectivity for the c-MYC G4.
• To investigate the binding mode and efficacy of these ligands in stabilizing the c-MYC G4.
• To evaluate the therapeutic potential of the optimal ligand against TNBC in vitro and in vivo.

Main Methods:

• Design and synthesis of imidazole-biphenyl analogs with tandem aromatic rings.
• Assessment of ligand binding affinity and selectivity for c-MYC G4 using biophysical methods.
• Evaluation of c-MYC expression inhibition, DNA damage induction, and cell cycle effects (G2/M arrest, apoptosis, autophagy).
• Testing antitumor efficacy in a TNBC xenograft mouse model.

Main Results:

• A series of conformation-tunable imidazole-biphenyl analogs were synthesized.
• The optimal ligand demonstrated superior stabilization of c-MYC G4 over other G4s, potentially via multi-site binding.
• The ligand effectively inhibited c-MYC expression, induced significant DNA damage, and triggered G2/M arrest, apoptosis, and autophagy.
• Significant antitumor activity was observed in a TNBC xenograft model.

Conclusions:

• Selective small-molecule ligands targeting c-MYC G4 can be developed using linked aromatic ring strategies.
• The optimal imidazole-biphenyl analog shows promise as an anti-TNBC agent by inhibiting c-MYC and inducing tumor cell death.
• This study provides a foundation for developing novel, selective G4-targeting therapeutics for TNBC.