Efforts to Develop KRAS Inhibitors
Open accessAbstract
The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists.Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable.However, recent progress in in silico screening, fragmentbased drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS.This review will cover some of the historical efforts to identify RAS inhibitors, and some of the most promising efforts currently being pursued.T he age of whole-genome sequencing has paved the road for "personalized" medicine in oncology.The Cancer Genome Atlas Research Network (2017), the Cancer Cell Line Encyclopedia (Barretina et al. 2012), the Genomics of Drug Sensitivity in Cancer (Yang et al. 2013), and similar efforts aim to catalog driver mutations with actionable and effective treatment regimens.While significant progress has been made in some notable areas, including BRAF-mutated melanomas (Davies et al. 2002;Chapman et al. 2011) and BRCA-mutated breast and ovarian cancers (Fong et al. 2009; The Cancer Genome Atlas Research Network 2011), many of the most common oncogenes were identified decades ago and remain the most deadly and elusive oncology drug targets.Perhaps chief among these is KRAS.Interest in KRAS as a cancer target stems from work with rodent sarcoma viruses in the late 1970s.First, DNAs from viruses and later from human tumor cells were shown to be sufficient to transform NIH-3T3 cells in culture (Shih et al. 1979;Shih et al. 1981).It was not until the early 1980s that KRAS was identified as the causative oncogene (Der et al. 1982;Parada and Weinberg 1983).By 1987, KRAS oncogenes were cloned from multiple tumor biopsies of lung, colon, and pancreas cancers (Santos et al. 1984;Bos et al. 1987;Forrester et al. 1987;Rodenhuis et al. 1987;Almoguera et al. 1988).By this time, all three RAS isoforms, H-, N-, and K-RAS were known and mutations at codons 12, 13, and 61 of a RAS isoform were shown to be sufficient to induce cell-cycle progression.Finally, the HRAS crystal structure revealed that the cancerassociated mutations at codons G12, G13, and Q61 are each located at a site of guanosine triphosphate (GTP) binding, suggesting a common mechanism of oncogenesis (Pai et al. 1989).
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For many proteins known to be involved in driving diseases, such as KRAS in many cancers, conventional drug development strategies often aimed at developing inhibitors have failed.
“For many proteins known to be involved in driving diseases, such as KRAS in many cancers, conventional drug development strategies often aimed at developing inhibitors have failed [118, 119].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [118]
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Oncogenic stress response mechanisms as new therapeutic targets in cancer treatment: A review
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Differential Response and Resistance to KRAS-Targeted Therapy
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- Authors
- Holderfield, M.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Holderfield, Matthew
- ORCID
- Holderfield, Matthew
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-11-03
- Volume
- 8
- Issue
- 7
- Pages
- a031864
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC6027934
- OpenAlex
- W2766621097
- Cited by
- 43
- References
- 55
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 5
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services (HHSN261200800001E)
- National Institutes of Health (Contract No. HHSN261200800001E., #HHSN261200800001E, HHSN261200800001C)
- National Cancer Institute (No. HHSN261200800001E, Contract No.,HHSN261200800001E, HHSN261200800001E))
- 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 inhibitors, KRAS mutation, oncogenic Ras, small molecule inhibitors, fragment-based drug discovery, virtual screening, KRAS G12C inhibitors, KRAS G12D inhibitors
- MeSH terms
- Antineoplastic Agents, Enzyme Inhibitors, Humans, Neoplasms, Endopeptidases, Protease Inhibitors, Drug Design, Signal Transduction, Proto-Oncogene Proteins p21(ras), Dimerization, Cyclic Nucleotide Phosphodiesterases, Type 6, Protein Multimerization
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