Pan-KRAS inhibitor disables oncogenic signalling and tumour growth

Abstract KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients 1–7 . Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary…

• 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
• NI
  National Institutes of Health

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

  Awards: CA008748, P30 CA008748