6V5N

EGFR(T790M/V948R) in complex with LN2084

Summary for 6V5N

• Entry DOI: 10.2210/pdb6v5n/pdb
• Descriptor: Epidermal growth factor receptor, 3-[4-(4-fluorophenyl)-5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-imidazol-2-yl]propan-1-ol, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: egfr, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 151709.12

Authors

Heppner, D.E.,Eck, M.J. (deposition date: 2019-12-04, release date: 2020-04-22, Last modification date: 2023-10-11)

Primary citation

Heppner, D.E.,Gunther, M.,Wittlinger, F.,Laufer, S.A.,Eck, M.J.
Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
J.Med.Chem., 63:4293-4305, 2020

PubMed Abstract: 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.

PubMed: 32243152
DOI: 10.1021/acs.jmedchem.0c00200

Experimental method

X-RAY DIFFRACTION (2.4 Å)