Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants.

Over the last two decades epidermal growth factor receptor (EGFR) kinase has become an important target to treat nonsmall cell lung cancer (NSCLC). Currently, three generations of EGFR kinase-targeted small molecule drugs have been FDA approved. They nominally produce a response at the start of treatment and lead to a substantial survival benefit for patients. However, long-term treatment results in acquired drug resistance and further vulnerability to NSCLC. Therefore, novel EGFR kinase inhibitors that specially overcome acquired mutations are urgently needed. To this end, we carried out a comprehensive study of different EGFR kinase mutants using a structural systems pharmacology strategy. Our analysis shows that both wild-type and mutated structures exhibit multiple conformational states that have not been observed in solved crystal structures. We show that this conformational flexibility accommodates diverse types of ligands with multiple types of binding modes. These results provide insights for designing a new generation of EGFR kinase inhibitor that combats acquired drug-resistant mutations through a multiconformation-based drug design strategy.