Covalent targeting of acquired cysteines in cancer
Open accessAbstract
The thiolate side chain of cysteine has a unique functionality that drug hunters and chemical biologists have begun to exploit. For example, targeting cysteine residues in the ATP-binding pockets of kinases with thiol-reactive molecules has afforded increased selectivity and potency to drugs like imbrutinib, which inhibits the oncogene BTK, and CO-1686 and AZD9291 that target oncogenic mutant EGFR. Recently, disulfide libraries and targeted GDP-mimetics have been used to selectively label the G12C oncogenic mutation in KRAS. We reasoned that other oncogenes contain mutations to cysteine, and thus screened the Catalog of Somatic Mutations in Cancer for frequently acquired cysteines. Here, we describe the most common mutations and discuss how these mutations could be potential targets for cysteine-directed personalized therapeutics.
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Common mutation sites in KRAS include codons 12, 13 and 61, with codon 12 being the most common mutation site.
“Common mutation sites in KRAS include codons 12, 13 and 61, with codon 12 being the most common mutation site.46–48”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [48]
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- Authors
- Visscher, M., Arkin, M. R., & Dansen, T. B.
- Affiliations
- University Medical Center Utrecht (NL)
- University of California, San Francisco (US)
- Corresponding author
- Arkin, Michelle R
- Dansen, Tobias B
- Venue
- Current Opinion in Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 30
- Pages
- 61-67
- ISSN
- 1367-5931 (ISSN-L)
- PMC
- PMC4731306
- OpenAlex
- W2187318534
- Cited by
- 95
- References
- 33
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 12 · 2022: 7 · 2021: 12 · 2020: 14 · 2019: 8 · 2018: 9 · 2017: 5 · 2016: 4
- FWCI
- 0.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Dutch Cancer Society
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Sulfur-Based Synthesis Techniques
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- somatic mutations, oncogenic mutations, kinase inhibitors, BTK inhibitors, EGFR inhibitors, KRAS G12C, personalized treatment
- MeSH terms
- Cysteine, Humans, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras), Precision Medicine, Molecular Targeted Therapy
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