Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design

[Graphics] Targeting KRAS-PDE delta protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDE delta inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle these challenges, herein, novel, highly potent KRAS-PDE delta inhibitors were identified by fragment-based drug design, providing promising lead compounds or chemical probes for investigating the biological functions and druggability of KRAS-PDE delta interaction.