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. 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. While GTP-OFF inhibitors of KRASG12C which bind to a switch-II have demonstrated clinical efficacy (including 2020 Small Molecule of the Year Finalist, MRTX849), resistance to such inhibitors was inevitable due to switch- II mutations. Because RM-018 targets the GTP-ON state of KRASG12C with a unique mechanism, it overcomes GTP-OFF resistance mutations such as KRASG12C/Y96D in patient-derived xenografts. While the discovery story hasn’t been published, based on the cyclophilin- binding MoA and structure it’s likely…