Identification of Novel pan-KRAS Inhibitors via Structure-Based Drug Design, Scaffold Hopping, and Biological Evaluation

KRAS is one of the most frequently mutated oncogenes in human cancers. Discovery of the allosteric binding sites next to the switch II loop triggered the successful development of KRAS-targeting therapeutic agents featuring different modalities. pan-KRAS inhibitors are of particular interest due to the broader scope of clinical indications and potential to overcome certain types of emerging resistance typical of allele-specific KRAS modulators. Herein, we explore the chemical space around MRTX1133, a compound with selectivity toward the KRAS^G12D variant, aiming to find new chemotypes with the potential to derive a clinical candidate. A series of novel pan-KRAS inhibitors with a potency in the upper nanomolar range have been developed. The inhibitory activity was demonstrated against key oncogenic KRAS mutants and a wild-type protein.