Discovery of Novel Inhibitors for WD Repeat-Containing Protein 5 (WDR5)-MYC Protein-Protein Interaction

Area of Science:

• Oncology
• Medicinal Chemistry
• Structural Biology

Background:

• The interaction between WD Repeat-Containing Protein 5 (WDR5) and MYC is vital for MYC-mediated oncogenesis.
• Current therapeutic strategies targeting WDR5 have shown limited efficacy, necessitating novel approaches.

Purpose of the Study:

• To discover and develop novel inhibitors of the WDR5-MYC protein-protein interaction (PPI).
• To identify compounds with improved potency and drug-like properties for potential cancer therapy.

Main Methods:

• Utilized a generative chemistry platform combined with a physics-model-based tool (AlChemistry).
• Identified initial hits with reasonable WDR5 binding affinity.
• Performed detailed structural analysis for compound refinement.

Main Results:

• Discovered novel WDR5-MYC PPI inhibitors.
• Achieved sub-micromolar affinity compounds, exemplified by compound 9c-1.
• The newly developed inhibitors demonstrated over 30-fold improvement in potency compared to previously reported agents.

Conclusions:

• The study presents promising novel inhibitors targeting the WDR5-MYC interaction.
• These findings offer a potential new therapeutic strategy for cancers driven by MYC.
• The developed compounds serve as a strong foundation for further drug development.