From KRAS G12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

KRAS, a significant oncology target, has been challenging to develop drugs for until recent discoveries of KRAS G12C mutant-specific covalent inhibitors, including MK-1084. This article describes efforts toward the discovery of KRAS G12D mutant-specific inhibitors and how synthetic innovations and structure-based drug design were utilized to facilitate the discovery of pan-KRAS inhibitors.