Cited by 281Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchProtease and Inhibitor Mechanisms

Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance

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Schwartz, Phillip A., Kuzmic, Petr, Solowiej, James, Bergqvist, Simon, Bolanos, Ben, Almaden, Chau, Nagata, Asako, Ryan, Kevin +6 more·2014·Proceedings of the National Academy of Sciences

Abstract

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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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
Venue
Proceedings of the National Academy of Sciences
Published
2013-12-17
Volume
111
Issue
1
Pages
173-178
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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