Discovery of EGF Receptor Inhibitors That Are Selective for the d746‐750/T790M/C797S Mutant through Structure‐Based de Novo Design

Next‐generation epidermal growth factor receptor (EGFR) inhibitors against the d746‐750/T790M/C797S mutation were discovered through two‐track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2‐aryl‐4‐aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746‐750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000‐fold selectivity for the d746‐750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.