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

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.

不可逆的酪氨酸激酶抑制剂（TKIs），如铂利尼布、WZ4002、HPI-272、卡培他滨和阿法替尼，与EGFR的半胱氨酸残基C397形成共价键，从而抑制对非共价TKIs耐药的突变体的自磷酸化。然而，共价TKIs的有效浓度也会抑制野生型EGFR，导致严重的副作用。因此，共价TKIs在治疗学领域并未展现出显著的潜力。