K-Ras protein as a drug target
Open accessAbstract
K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K-Ras protein from a structural perspective, making therapeutic attack extremely challenging. K-Ras is a member of a large family of related proteins, which share very similar GDP/GTP-binding domains, making specific therapies more difficult. Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K-Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non-canonical Wnt signaling.
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KRAS is a member of the guanine nucleotide-binding protein family and cycles between an inactive GDP-bound state and an active GTP-bound state.
“KRAS is a member of the guanine nucleotide-binding protein family [4] and cycles between an inactive guanosine diphosphate (GDP)-bound state (“off”) and an active guanosine triphosphate (GTP)-bound state (“on”).”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [4]
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- Authors
- McCormick, F.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- McCormick, Frank
- ORCID
- McCormick, Frank
- Venue
- Journal of Molecular Medicine
- Published
- 2016-03
- Volume
- 94
- Issue
- 3
- Pages
- 253-258
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC4803814
- OpenAlex
- W2295798984
- Cited by
- 105
- References
- 30
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 16 · 2018: 15 · 2017: 17 · 2016: 2
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- 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 › Melanoma and MAPK Pathways
- Keywords
- KRAS, Ras GTPase, oncogenic Ras, cancer, therapeutic target, GTP-bound state, post-translational modification, calmodulin binding, non-canonical Wnt signaling, RAS inhibitors
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Models, Molecular, Neoplasms, Protein Processing, Post-Translational, ras Proteins, Drug Discovery, Molecular Targeted Therapy, Protein Interaction Maps
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