Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors

J Med Chem. 2020 Apr 23;63(8):4293-4305. doi: 10.1021/acs.jmedchem.0c00200. Epub 2020 Apr 14.


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 "αC-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Crystallography, X-Ray
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Genetic Variation / drug effects
  • Genetic Variation / genetics*
  • Imidazoles / antagonists & inhibitors*
  • Imidazoles / metabolism
  • Mutation / drug effects
  • Mutation / genetics*
  • Protein Structure, Secondary
  • Sf9 Cells


  • Antineoplastic Agents
  • Imidazoles
  • EGFR protein, human
  • ErbB Receptors