Structural Insights into Drug Development Strategy Targeting EGFR T790M/C797S

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Mar 24

PMID 29568384

Citations 13

Authors

Su-Jie Zhu

Peng Zhao

Jiao Yang

Rui Ma

Xiao-E Yan

Sheng-Yong Yang

Jing-Wen Yang

Cai-Hong Yun

Affiliations

Soon will be listed here.

Abstract

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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