molecules of the month

The Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in a tri-complex (KRAS- inhibitor-cyclophilin A) stabilized by protein-protein interactions. An undisclosed molecule in their pipeline with a related mechanism, RMC-6291, has been reported to be orally bioavailable in multiple species, with oral activity in PDX models. KRAS is a driver of cancer cell growth, and mutants including KRASG12C have been hot targets due to the newfound ability to drug them selectively over wild type KRAS, which is important for healthy cell division. The first KRASG12C inhibitor, sotorasib, was approved in 2021. While GTP-OFF inhibitors of KRASG12C which bind to a switch-II have demonstrated clinical efficacy (including 2020 Small Molecule of the Year Finalist,…