Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance
Open accessAbstract
Significance: Covalent kinase inhibition strategies are reemerging, but critical gaps in the understanding of molecular determinants of potency still persist. A kinetic approach is developed to describe the components of overall inhibitor potency (reversible binding and chemical reactivity). Detailed kinetic descriptions of EGFR covalent drugs are provided. Reversible interactions of covalent inhibitors are found to be essential to biochemical and cellular potency. A dynamic linkage between available affinity and necessary reactivity is proposed. Cysteine oxidation is an emerging type of posttranslational modification. Specific oxidation of the EGF receptor cysteine nucleophile causes highly variable effects on inhibitor potency. Two mechanisms of drug resistance are identified (reversible cysteine–inhibitor warhead interactions and specific cysteine oxidation) as well as a rational framework for understanding and designing covalent inhibitors.
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Overcoming toxicity is one of the main bottlenecks preventing covalent inhibitors from entering the market.
“Overcoming toxicity is one of the main bottlenecks preventing covalent inhibitors from entering the market [140].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [140]
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- Authors
- Schwartz, P. A., Kuzmic, P., Solowiej, J., Bergqvist, S., Bolanos, B., Almaden, C., Nagata, A., Ryan, K., Feng, J., Dalvie, D., Kath, J. C., Xu, M., Wani, R., & Murray, B. W.
- Affiliations
- Pfizer (United States) (US)
- Research and Development, BioKin Ltd., Watertown, MA 02472
- Oncology Research Unit,
- Worldwide Medicinal Chemistry, and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-12-17
- Volume
- 111
- Issue
- 1
- Pages
- 173-178
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3890870
- OpenAlex
- W2131964519
- Cited by
- 281
- References
- 50
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 22 · 2023: 13 · 2022: 19 · 2021: 21 · 2020: 41 · 2019: 22 · 2018: 22 · 2017: 22 · 2016: 26 · 2015: 20 · 2014: 11
- FWCI
- 16.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- covalent inhibitors, EGFR inhibitors, drug resistance, cysteine oxidation, sulfinylation, enzyme kinetics, inhibitor potency, kinase inhibitor design, oncogenic mutations
- MeSH terms
- Antineoplastic Agents, Catalysis, Chemistry, Pharmaceutical, Cysteine, Drug Resistance, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Humans, Oxygen, Phosphorylation, Protein Binding, Protein Conformation, Quinazolines, Mass Spectrometry, Drug Design, Signal Transduction, Inhibitory Concentration 50, Cell Line, Tumor, ErbB Receptors
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