Research Papers:

Structural basis of mutant-selectivity and drug-resistance related to CO-1686

Xiao-E Yan, Su-Jie Zhu, Ling Liang, Peng Zhao, Hwan Geun Choi and Cai-Hong Yun _

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Oncotarget. 2017; 8:53508-53517. https://doi.org/10.18632/oncotarget.18588

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Xiao-E Yan1,2,*, Su-Jie Zhu1,2,*, Ling Liang1,2, Peng Zhao1,2, Hwan Geun Choi3,4 and Cai-Hong Yun1,2

1Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

2Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

3Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA

4Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA

*These authors have contributed equally to this work

Correspondence to:

Cai-Hong Yun, email: [email protected]

Keywords: NSCLC, EGFR kinase, T790M, CO-1686, structural pharmacology

Received: March 31, 2017     Accepted: May 08, 2017     Published: June 21, 2017


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.

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