Proteome-wide Identification of Off-Targets of a Potent EGFRL858R/T790M Mutant Inhibitor

Peng Lyu; Kaili Jiang; Yuee Zhou; Jun Hu; Yu Chang; Zhang Zhang; Minhao Huang; Zhi-Min Zhang; Ke Ding; Piliang Hao; Ligen Lin; Zhengqiu Li

doi:10.1021/acsmedchemlett.1c00651

Proteome-wide Identification of Off-Targets of a Potent EGFR^L858R/T790M Mutant Inhibitor

ACS Med Chem Lett. 2022 Jan 19;13(2):292-297. doi: 10.1021/acsmedchemlett.1c00651. eCollection 2022 Feb 10.

Authors

Peng Lyu¹, Kaili Jiang², Yuee Zhou², Jun Hu², Yu Chang², Zhang Zhang², Minhao Huang², Zhi-Min Zhang², Ke Ding², Piliang Hao³, Ligen Lin¹, Zhengqiu Li²

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China.
² School of Pharmacy, Jinan University, Guangzhou 510632, China.
³ School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.

Abstract

Target identification is an essential step in drug discovery. It facilitates an understanding of drug action and potential toxicities and offers opportunities to repurpose drug candidates. HP-1, a potent EGFR^L858R/T790M (epidermal growth factor receptor) mutant inhibitor, was developed by the group in an effort to treat acquired resistance in nonsmall cell lung cancer (NSCLC), but its cellular off-targets were not identified. An activity-based probe, HJ-1, was created followed by chemical proteomics and bioimaging studies. A total of 13 protein hits, including EGFR and NT5DC1, were identified by pull-down/LC-MS. Subsequent validation experiments indicated the involvement of a major off-target, NT5DC1, in the biological function of HP-1.