Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
Open accessAbstract
The Ras gene is frequently mutated in cancer, and mutant Ras drives tumorigenesis. Although Ras is a central oncogene, small molecules that bind to Ras in a well-defined manner and exert inhibitory effects have not been uncovered to date. Through an NMR-based fragment screen, we identified a group of small molecules that all bind to a common site on Ras. High-resolution cocrystal structures delineated a unique ligand-binding pocket on the Ras protein that is adjacent to the switch I/II regions and can be expanded upon compound binding. Structure analysis predicts that compound-binding interferes with the Ras/SOS interactions. Indeed, selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation by blocking the formation of intermediates of the exchange reaction. The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein.
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Recently, three studies used similar fragment-based small molecule screening to identify compounds that bind sites on the K-Ras surface and block its SOS-mediated activation.
“Recently, three studies used similar fragment-based small molecule screening to identify compounds that bind sites on the K-Ras surface and block its SOS-mediated activation24–26 suggesting the approach has some promise.”
From Discovery and characterization of small molecules that target the GTPase Ral (2014) · cites this paper as [25]
DCAI binds to a unique pocket adjacent to the switch I/II region of Ras and interferes with the interaction between Ras and SOS1.
“4,6-Dichloro-2-methyl-3-aminoethyl-indole (DCAI) is another group of compounds that bind to a unique pocket adjacent to the switch I/II region of Ras and interfere with the interaction between Ras and SOS1.47”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [47]
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Parker, M. I., Meyer, J. E., Golemis, E. A., & Dunbrack (2023) · doi:10.1158/0008-5472.c.6513960
- Authors
- Maurer, T., Garrenton, L. S., Oh, A., Pitts, K., Anderson, D. J., Skelton, N. J., Fauber, B. P., Pan, B., Malek, S., Stokoe, D., Ludlam, M. J. C., Bowman, K. K., Wu, J., Giannetti, A. M., Starovasnik, M. A., Mellman, I., Jackson, P. K., Rudolph, J., Wang, W., & Fang, G.
- Affiliations
- Genentech (US)
- Research Oncology,
- Structural Biology,
- Biochemical and Cellular Pharmacology,
- Corresponding author
- Fang, Guowei
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-03-19
- Volume
- 109
- Issue
- 14
- Pages
- 5299-5304
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3325706
- OpenAlex
- W2146926552
- Cited by
- 618
- References
- 21
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 38 · 2023: 32 · 2022: 48 · 2021: 40 · 2020: 56 · 2019: 55 · 2018: 48 · 2017: 48 · 2016: 43 · 2015: 51 · 2014: 47 · 2013: 43 · 2012: 18
- FWCI
- 21.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Ras, small molecule inhibitors, binding pocket, SO, nucleotide exchange, Ras activation, fragment screening, co-crystal structure, oncogenic Ras, cancer therapeutics
- MeSH terms
- Binding Sites, Cell Line, Humans, Ligands, Models, Molecular, Nucleotides, ras Proteins, Nuclear Magnetic Resonance, Biomolecular, Son of Sevenless Proteins
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