A neomorphic protein interface catalyzes covalent inhibition of RAS <sup>G12D</sup> aspartic acid in tumors
Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended pharmacodynamic effect, but covalent targeting of RAS<sup>G12D</sup> is hindered by low nucleophilicity and high proteomic abundance of carboxylic acids. We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRAS<sup>G12D</sup> cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).
Authors
- Junning Wang (ORCID: https://orcid.org/0000-0002-5559-9343)
- Melissa M. Ronan (ORCID: https://orcid.org/0000-0003-4269-1404)
- Anthony N. Milin (ORCID: https://orcid.org/0000-0002-1923-7441)
- Abby Marquez (ORCID: https://orcid.org/0000-0001-5104-2823)
- Benjamin J. Maldonato (ORCID: https://orcid.org/0000-0001-6560-0224)
- Hanrong Feng (ORCID: https://orcid.org/0000-0002-2133-5374)
- Diane F. Eilerts (ORCID: https://orcid.org/0000-0002-8062-108X)
- Connor J. Hennessey (ORCID: https://orcid.org/0000-0002-5579-1220)
- Matthew Holderfield (ORCID: https://orcid.org/0000-0001-8474-3220)
- Adrian L. Gill (ORCID: https://orcid.org/0009-0003-0914-4860)
- Eejung Kim (ORCID: https://orcid.org/0000-0003-0381-0992)
- Jacqueline A.M. Smith (ORCID: https://orcid.org/0000-0001-5028-8725)
- G. Leslie Burnett (ORCID: https://orcid.org/0000-0003-2514-9373)
- Julien Dilly (ORCID: https://orcid.org/0000-0002-4006-5285)
- Sujata Chakraborty (ORCID: https://orcid.org/0000-0003-0080-3180)
- Seema Chugh (ORCID: https://orcid.org/0000-0003-1486-0725)
- David Wildes (ORCID: https://orcid.org/0009-0009-3855-7270)
- Kyle J. Seamon (ORCID: https://orcid.org/0009-0005-5028-3752)
- Elena S. Koltun (ORCID: https://orcid.org/0009-0005-8720-9097)
- Shelby L. Steele (ORCID: https://orcid.org/0000-0001-8816-4752)
- John E. Knox (ORCID: https://orcid.org/0009-0006-6246-5198)
- Brian M. Wolpin (ORCID: https://orcid.org/0000-0002-0455-1032)
- Nicole A. Vita (ORCID: https://orcid.org/0000-0003-4985-6662)
- Jennifer A. Roth (ORCID: https://orcid.org/0000-0002-5117-5586)
- Jingjing Jiang (ORCID: https://orcid.org/0009-0004-2766-025X)
- Zhican Wang (ORCID: https://orcid.org/0000-0002-9411-9349)
- Jessica N. Spradlin (ORCID: https://orcid.org/0000-0001-7278-6645)
- Mallika Singh (ORCID: https://orcid.org/0009-0003-0234-1589)
- William C. Hahn (ORCID: https://orcid.org/0000-0003-2840-9791)
- Matthew G. Rees (ORCID: https://orcid.org/0000-0002-2987-7581)
- Andrew J. Aguirre (ORCID: https://orcid.org/0000-0002-0701-6203)
- Caroline E. Weller
- Lingyan Jiang (ORCID: https://orcid.org/0009-0006-7523-6968)
- Ciara Helland
- Tamar Bar Ziv (ORCID: https://orcid.org/0009-0008-1751-8507)
- Dongyu Zhang (ORCID: https://orcid.org/0000-0001-9125-816X)
- Zhengping Wang (ORCID: https://orcid.org/0000-0001-5928-3816)
- Phuong Uyen Dinh
- Yunming Mu
- Andrea Gould
Institutions
- Broad Institute (US)
- Harvard University (US)
- Revolution Medicines (United States) (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Science
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1126/science.ads0239
- Citations
- 22
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 17.73