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

Stable Identifier
Reaction [binding]
Homo sapiens
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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
20966921 Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Pao, W, Chmielecki, J

Nat Rev Cancer 2010
20033049 Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

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

Nature 2009
Participant Of
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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