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Publication Abstract from PubMed

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 led 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 "alphaC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.

Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.,Heppner DE, Gunther M, Wittlinger F, Laufer SA, Eck MJ J Med Chem. 2020 Apr 14. doi: 10.1021/acs.jmedchem.0c00200. PMID:32243152^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.