Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors

Stable Identifier
R-HSA-1220611
Type
Reaction [binding]
Species
Homo sapiens
Compartment
plasma membrane, cytosol, extracellular region
ReviewStatus
5/5
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Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors
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Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs. However, effective concentrations of covalent TKIs also inhibit wild type EGFR, resulting in severe side effects. Hence, covalent TKIs have not shown much promise as therapeutics.
Literature References
PubMed ID Title Journal Year
20033049 Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

Zhou, W, Eck, MJ, Cortot, AB, Jänne, PA, Capelletti, M, Li, D, Padera, R, Engen, JR, Chen, L, Chirieac, L, Gray, NS, Iacob, RE, Wong, KK, Yun, CH, Ercan, D

Nature 2009
20966921 Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Chmielecki, J, Pao, W

Nat Rev Cancer 2010
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Orlic-Milacic, M  (2011-11-04)
Reviewed
Greulich, H  (2011-11-15)
Savas, S  (2011-11-15)
Created
Orlic-Milacic, M  (2011-02-23)
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