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

The WD Repeat-Containing Protein 5 (WDR5) and MYC interaction is crucial for MYC-mediated oncogenesis, yet effective therapeutic intervention remains challenging due to the limited efficacy of current treatments targeting WDR5. Herein, we report the discovery of novel WDR5-MYC protein-protein interaction (PPI) inhibitors with improved potency and drug-like properties by utilizing a generative chemistry platform along with a physics-model-based tool AlChemistry. Initially, three hits were identified with reasonable binding affinity for WDR5, and further refinement through detailed structural analysis led to the discovery of sub-micromolar affinity compounds (compound 9c-1), which are > 30-fold better than reported inhibitors. These findings provide a promising starting point for targeting the WDR5-MYC interaction in MYC-driven cancers.

MYC; PPI; WDR5; generative chemistry; physics‐model‐based tool.