Drugging all RAS isoforms with one pocket

Activating mutations in the three human RAS genes, KRAS, NRAS and HRAS, are among the most common oncogenic drivers in human cancers. Covalent KRAS G12C inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS G12C -driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.