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

ABSTRACT 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.