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editorial
. 2015 Dec 18;7(1):2–5. doi: 10.1021/acsmedchemlett.5b00475

Figure 2.

Figure 2

Binding mode of covalent EGFR tyrosine kinase inhibitors. The binding equilibrium indicates, whether the binding of ligand (L) and receptor (R) is favored. (A) The emergence of the T790M gatekeeper mutation induces steric hindrance of 4-aminoquinazolines such as afatinib with the methionine side chain (highlighted in red) and promotes the dissociation of the reversible ligand and receptor complex [LR]. Therefore, covalent bond formation (highlighted in yellow) of second-generation inhibitors with the receptor, yielding the covalent adduct L–R, cannot sufficiently occur (PDB code: 4G5P). (B) Third-generation TKIs, as exemplified by the structural analogue WZ4002, avoid the steric conflict with Met790 and therefore achieve complete receptor occupancy (PDB code: 3IKA). (C) The C797S mutation mediates resistance to irreversible drugs since the less nucleophilic serine side chain cannot undergo covalent bond formation (highlighted in red) at physiological conditions (model based on PDB code: 3IKA).