Abstract:

<p>Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors lead to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the &quot;αC-helix out&quot; inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, non-covalent inhibition of C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small cell lung cancer.</p>