Structure-based drug design of small-molecule c-Myc G-quadruplex binders

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The c-Myc oncogene plays a critical role in cancer development.
• c-Myc's protein structure lacks a druggable pocket, posing a challenge for direct therapeutic targeting.
• The c-Myc promoter can form G-quadruplex (G4) structures, offering an indirect inhibition strategy.

Purpose of the Study:

• To identify small molecules that bind to the c-Myc G-quadruplex (G4) structure.
• To evaluate the potential of these molecules as therapeutic agents for cancer, specifically multiple myeloma.
• To establish a foundation for developing novel anticancer drugs targeting the c-Myc G4.

Main Methods:

• Structure-based virtual screening of the ChemDiv compound library using the c-Myc G4 crystal structure.
• In vitro assays to evaluate the biological activity of candidate compounds.
• Assessment of Y502-3888's effect on c-Myc mRNA and protein expression levels.

Main Results:

• The compound Y502-3888 was identified as a binder to the c-Myc G4 structure.
• Y502-3888 effectively downregulates c-Myc expression at both mRNA and protein levels.
• Preliminary in vitro assays confirmed the biological activity of Y502-3888.

Conclusions:

• Y502-3888 demonstrates potential as a c-Myc G4 binder for treating multiple myeloma (MM).
• This study provides a basis for developing new anticancer agents targeting the c-Myc G4 structure.
• The findings highlight a promising new avenue for targeting the previously "undruggable" c-Myc oncogene.