Targeting a c-MYC G-quadruplex DNA with a fragment library

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• The human c-MYC gene is a proto-oncogene crucial for cell growth and proliferation.
• Dysregulation of c-MYC is implicated in various cancers, making it a significant therapeutic target.
• G-quadruplex structures in promoter regions, like that of c-MYC, offer unique binding sites for small molecules.

Purpose of the Study:

• To screen a fragment library for compounds that bind to the G-quadruplex in the human c-MYC promoter.
• To validate the identified fragment hits using biophysical and cellular assays.
• To assess the feasibility of a fragment-based drug discovery approach for targeting nucleic acid structures.

Main Methods:

• Fragment library screening against the c-MYC G-quadruplex.
• Utilized biophysical assays to confirm fragment binding.
• Employed in silico modeling to predict binding interactions.
• Assessed the effect of fragments on c-MYC gene expression in cellular models.

Main Results:

• Ten fragment hits were identified with significant binding to the c-MYC G-quadruplex.
• Concordance was observed between biophysical assay results, in silico predictions, and observed inhibition of c-MYC expression.
• The identified fragments demonstrated the potential to modulate c-MYC activity.

Conclusions:

• Fragment-based screening is a viable strategy for discovering ligands that target G-quadruplex structures.
• This approach can lead to the development of novel therapeutics for cancers driven by c-MYC.
• Targeting nucleic acid structures like G-quadruplexes represents a promising frontier in drug discovery.