5XDL

Crystal structure of EGFR 696-1022 L858R in complex with CO-1686

Summary for 5XDL

• Entry DOI: 10.2210/pdb5xdl/pdb
• Related: 5XDK
• Descriptor: Epidermal growth factor receptor, N-[3-[[2-[[4-(4-ethanoylpiperazin-1-yl)-2-methoxy-phenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide (3 entities in total)
• Functional Keywords: egfr, l858r, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38236.03

Authors

Yan, X.E.,Zhu, S.J.,Yun, C.H. (deposition date: 2017-03-28, release date: 2017-12-13, Last modification date: 2024-11-13)

Primary citation

Yan, X.E.,Zhu, S.J.,Liang, L.,Zhao, P.,Choi, H.G.,Yun, C.H.
Structural basis of mutant-selectivity and drug-resistance related to CO-1686.
Oncotarget, 8:53508-53517, 2017

PubMed Abstract: Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs. Despite the remarkable success, the experimentally determined structure of this agent in complex with EGFR T790M remains unknown. In this study, we determined crystal structures of EGFR T790M or L858R mutants covalently bound by CO-1686. Based on these structural data, we can explain why CO-1686 irreversibly inhibits EGFR and selectively prefers T790M, which may help improving this or similar compounds, and explain why EGFR L718Q and L844V mutations incur resistance to this agent.

PubMed: 28881827
DOI: 10.18632/oncotarget.18588

Experimental method

X-RAY DIFFRACTION (2.7 Å)