Revolution Medicines publishes zoldonrasib research in Science

Revolution Medicines (RVMD) announced the publication of a peer-reviewed research paper in Science. The scientific paper details the discovery and development of zoldonrasib, a RAS G12D-selective covalent inhibitor. Oncogenic RAS mutations are observed in approximately 92% of pancreatic ductal adenocarcinoma, 50% of colorectal cancer, and 30% of non-small cell lung cancer cases. RAS G12D, an oncogenic variant of RAS that contains an aspartic acid in place of glycine at amino acid 12, is one of the most common RAS mutations in human solid tumors. Historically, it has been particularly challenging to target aspartic acid residues with covalent inhibitors. This publication details the novel mechanism of zoldonrasib, a member of the differentiated class of targeted protein binders called tri-complex inhibitors. This natural product-like compound successfully overcomes the challenge of engaging aspartic acid residues by leveraging a neomorphic protein-protein interface between the cellular chaperone cyclophilin A and activated RAS, or RAS, to selectively catalyze covalent bond formation with RAS G12D proteins. Data reported in this paper demonstrate that this activity drives deep and durable tumor regressions in preclinical models of multiple tumor types with KRAS G12D mutations.