On July 24, 2025 Revolution Medicines, Inc. (Nasdaq: RVMD), a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers, reported the publication of a peer-reviewed research paper in Science (Press release, Revolution Medicines, JUL 24, 2025, View Source [SID1234654504]). The scientific paper details the discovery and development of zoldonrasib (RMC-9805), a RAS(ON) G12D-selective covalent inhibitor.
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Oncogenic RAS mutations are observed in approximately 92% of pancreatic ductal adenocarcinoma (PDAC), 50% of colorectal cancer, and 30% of non-small cell lung cancer (NSCLC) 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(ON), to selectively catalyze covalent bond formation with RAS(ON) 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.
"The tri-complex inhibitor modality has proven to be a productive approach to solving the challenge of developing mutant-selective inhibitors for RAS variants beyond the G12C substitution, as demonstrated by zoldonrasib that targets the G12D variant," said Jan Smith, Ph.D., chief scientific officer of Revolution Medicines. "This report demonstrates the novel features of zoldonrasib that enable it to bind to the active or RAS(ON) state, including a highly novel covalent bond formed selectively with the substituted aspartic acid in this oncogenic variant. The preclinical profile combined with recent clinical data presentations provide an encouraging picture of the therapeutic potential for zoldonrasib in cancers caused by RAS G12D and further validate the broad utility of this drug discovery approach."
The full manuscript, titled "A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors," is available online at Science.
Zoldonrasib is currently undergoing evaluation in several clinical trials, including RMC-9805-001 (NCT06040541), a multicenter, open-label, dose escalation and dose-expansion Phase 1 study designed to evaluate zoldonrasib in patients with advanced solid tumors harboring a KRAS G12D mutation. NSCLC results from this study were presented in April 2025 at the American Academy for Cancer Research annual meeting and PDAC results from this study were presented in October 2024 at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics.