Drugging all RAS isoforms with one pocket
Activating mutations in the three human RAS genes—KRAS, NRAS, and HRAS—are among the most prevalent oncogenic drivers in human cancers. Covalent KRASG12C inhibitors, which bind to the switch II pocket in the “off state” of KRAS, represent the first direct KRAS-targeted drugs to enter human clinical trials. However, the remaining 85% of cancers not driven by KRASG12C, as well as those driven by NRAS and HRAS, remain undrugged, and no therapies targeting the “on state” of RAS have been identified. The switch I/II pocket offers another potential target, with the nanomolar inhibitor BI-2852 being one notable discovery. In this study, we explore the binding modes of inhibitors in KRAS, NRAS, and HRAS in both their “on” and “off” states, and discuss potential strategies for developing drugs that target all RAS isoforms through this pocket.