Abstact

NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a tool compound for further studies of NRAS biology. The development process revealed key insights into gaining selectivity between NRAS and KRAS proteins. Notably, stabilization of the p-loop and substitution toward Leu 95 while maintaining key interactions with Asp12, Gly60, and Asp69 improved NRAS G12D potency and resulted in selectivity against wild-type KRAS/non-responder.