Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo
Open accessAbstract
Ras mutations (e.g., occur in K-Ras, N-Ras, and H-Ras) are one of the most desirable and promising drug targets in chemotherapy treatments for cancer. However, there are still no approved drugs directly targeting mutated Ras. In 2017, an artificial cyclic peptide, KRpep-2d, was discovered as the first selective inhibitor of K-Ras(G12D), the most frequent K-Ras mutation. Here, we report the generation of KS-58, a KRpep-2d derivative that is identified as a bicyclic peptide and possess unnatural amino acid structures. Our in vitro data and molecular dynamics simulations suggest that KS-58 enters cells and blocks intracellular Ras–effector protein interactions. KS-58 selectively binds to K-Ras(G12D) and suppresses the in vitro proliferation of the human lung cancer cell line A427 and the human pancreatic cancer cell line PANC-1, both of which express K-Ras(G12D). Moreover, KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts. The anti-cancer activity is further improved by combination with gemcitabine. To the best of our knowledge, this is the first report of K-Ras(G12D)-selective inhibitory peptide presenting in vivo anti-cancer activity. KS-58 is an attractive lead molecule for the development of novel cancer drugs that target K-Ras(G12D).
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Sakamoto et al. developed KS-58, a KRAS G12D-selective inhibitory peptide.
“Sakamoto et al. have developed KS-58, a KRAS G12D-selective inhibitory peptide, which has gained considerable attention [79,80].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [79]
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Self-citation
- Authors
- Sakamoto, K., Masutani, T., & Hirokawa, T.
- Affiliations
- Ichimaru Pharcos (Japan) (JP)
- University of Tsukuba (JP)
- Corresponding author
- Sakamoto, Kotaro
- Venue
- Scientific Reports
- Published
- 2020-12-10
- Volume
- 10
- Issue
- 1
- Pages
- 21671-21671
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7730438
- OpenAlex
- W3111730301
- Cited by
- 85
- References
- 38
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 19 · 2022: 13 · 2021: 20
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion)
- Funders
- Japan Agency for Medical Research and Development (JP18am0101114)
- Papua New Guinea University of Technology
- 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 › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12D, bicyclic peptides, unnatural amino acids, lung cancer, pancreatic cancer, gemcitabine combination therapy, xenograft tumor growth, anticancer peptides
- MeSH terms
- Gemcitabine, Amino Acid Sequence, Animals, Antineoplastic Agents, Deoxycytidine, Drug Therapy, Combination, Lung Neoplasms, Mutation, Neoplasm Transplantation, Pancreatic Neoplasms, Peptides, Genes, ras, Cell Line, Tumor, Cell Proliferation, Mice, Rats, Molecular Targeted Therapy
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