Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer.
Wei LongBo-Xin ZhengYing LiXuan-He HuangDan-Min LinCui-Cui ChenJin-Qiang HouTian-Miao OuWing-Leung WongKun ZhangYu-Jing LuPublished in: Nucleic acids research (2022)
DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.
Keyphrases
- gene expression
- dna damage
- dna methylation
- high resolution
- induced apoptosis
- small molecule
- cell cycle arrest
- endothelial cells
- transcription factor
- oxidative stress
- dna binding
- breast cancer cells
- magnetic resonance
- machine learning
- cell death
- dna repair
- single molecule
- metabolic syndrome
- endoplasmic reticulum stress
- signaling pathway
- pi k akt
- cancer therapy
- living cells
- cell free
- structural basis
- nucleic acid
- drug induced