ABSTRACT c‐Myc ( MYC ) is an important member of the Myc‐proto‐oncogene family. MYC regulates a number of important physiological processes in cell. Normally, MYC level is regulated tightly, but it is overexpressed in various diseases, including cancer. Notably, the guanine (G) rich regions present in the promoter negatively regulate the transcription of MYC folding into a specific DNA secondary structure called G‐quadruplex (G4). Consequently, the repression of MYC transcription, targeting G4, is an appealing strategy for therapeutic intervention in cancer. Here, we have designed and synthesized tyrosine‐based ligands to target MYC G4. Various biophysical and biochemical studies have been employed to check the targeting ability of the ligands. The studies establish that the ligands not only can recognize MYC G4 but also can provide thermal stability upon complexation. In silico studies and dye displacement assay reveal that the ligands bind at the G4's loop. Moreover, the ligands can selectively inhibit the viability of triple‐negative breast cancer cells, MDA‐MB‐468 in vitro. The MYC protein expression level is also found to be downregulated in MDA‐MB‐468 cells after treatment with ligand. Overall, our studies provide a fertile guideline to design amino acid‐based MYC G4 ligands and majorly thrust the G4 targeting anticancer therapeutics research.
Basak et al. (Sun,) studied this question.