Background

A variety of tyrosine kinase inhibitors (TKIs) have been developed to target human epidermalgrowth factor receptor (EGFR) for non-small-cell lung cancer (NSCLC) therapy. However, many patientstreated with first-line TKIs are clinically observed to eventually establish a gatekeeper T790M mutation inEGFR active site, which plays a primary role in development of acquired resistance to TKIs.

Objective

Here, we attempted to investigate the intermolecular interactions of wild-type EGFR (EGFRWT)and its T790M mutant (EGFRT790M) with a number of culled reversible EGFR TKIs, paying attention to thestructural and energetic response of inhibitor ligands to the mutation.

Methods

A TKI panel consisting of 9 sophisticated EGFR inhibitors was manually culled, and an integrationof structural modeling, virtual mutagenesis, quantum mechanics/molecular mechanics analysis and bindingassay was performed to systematically examine the binding of these inhibitors to both wild-type and mutantEGFR.

Results

T790M-introduced steric hindrance plays a primary role in the acquired resistance to WT-selectiveinhibitors, whereas the mutation is observed to form additional noncovalent forces with WT-sparinginhibitors. Structural analysis reveals that the steric hindrance generally induces a conformational change ofWT-selective inhibitors in EGFR active site, while the weak noncovalent forces have only a moderate effecton the binding mode of WT-sparing inhibitors.

Conclusion

EAI045, the first fourth-generation EGFR inhibitor, exhibits a moderate affinity to EGFR andpossesses an exquisite selectivity for wild type over mutant kinase (~3-fold). This is expected if consideringthat the EAI045 is an allosteric inhibitor, which does not need to directly compete with ATP, and high affinityand selectivity are therefore not required for the inhibitor.