Revolution Medicines, Inc. announced on July 24, 2025, the publication of a peer-reviewed research paper in Science, detailing the discovery and development of zoldonrasib (RMC-9805), a RAS(ON) G12D-selective covalent inhibitor. The paper highlights the novel mechanism of zoldonrasib, a tri-complex inhibitor, in overcoming the challenge of targeting aspartic acid residues.
The publication describes how zoldonrasib leverages a neomorphic protein-protein interface between cyclophilin A and activated RAS (RAS(ON)) to selectively catalyze covalent bond formation with RAS(ON) G12D proteins. Data presented in the paper demonstrate that this activity drives deep and durable tumor regressions in preclinical models of multiple tumor types with KRAS G12D mutations.
This scientific validation underscores the broad utility of Revolution Medicines' drug discovery approach and the therapeutic potential for zoldonrasib in cancers caused by RAS G12D mutations. Zoldonrasib is currently undergoing evaluation in several clinical trials, with initial NSCLC results presented in April 2025 and PDAC results in October 2024.
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