Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS(G12C) (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS(G12C) tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS(G12C) or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

Automated summary

Researchers have designed a small molecule that has high affinity and selectivity for the active form of mutant KRAS, a difficult-to-target oncogene. This small molecule remodels the surface of a protein and inhibits oncogenic signaling, leading to tumor regressions in cancer models. This inhibitory strategy can be applied to other undruggable cancer drivers.