Structural insights into drug development strategy targeting EGFR T790M/C797S
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Su-Jie Zhu1,2,3,*, Peng Zhao1,2,3,*, Jiao Yang4, Rui Ma1,2,3, Xiao-E Yan1,2,3, Sheng-Yong Yang4,#, Jing-Wen Yang5,# and Cai-Hong Yun1,2,3
1Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
2Department of Biophysics and School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
3Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
4State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
5Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China
*These authors contributed equally to this work
Cai-Hong Yun, email: [email protected]
Keywords: lung cancer; T790M/C797S; drug resistance; x-ray crystallography; structure-based drug design
Received: July 12, 2017 Accepted: December 03, 2017 Published: January 10, 2018
Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.
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