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…

• PC
  Pew Charitable Trusts
• DR
  Damon Runyon Cancer Research Foundation

  Award: P30 CA008748
• MS
  Memorial Sloan-Kettering Cancer Center

  Award: CA008748
• PS
  Pershing Square Sohn Cancer Research Alliance

  Award: P30 CA008748
• RM
  Revolution Medicines
• NI
  National Institutes of Health

  Awards: 1R01CA23074501, P30 CA008748, 1R01CA23026701A1
• NC
  National Cancer Institute

  Awards: CA008748, P30 CA008748