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

被引：4

作者：

Lyu, Peng ^{[1
]}

Jiang, Kaili ^{[2
]}

Zhou, Yuee ^{[2
]}

Hu, Jun ^{[2
]}

Chang, Yu ^{[2
]}

Zhang, Zhang ^{[2
]}

Huang, Minhao ^{[2
]}

Zhang, Zhi-Min ^{[2
]}

Ding, Ke ^{[2
]}

Hao, Piliang ^{[3
]}

Lin, Ligen ^{[1
]}

Li, Zhengqiu ^{[2
]}

机构：

[1] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa 999078, Macau, Peoples R China

[2] Jinan Univ, Sch Pharm, Guangzhou 510632, Guangdong, Peoples R China

[3] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2022年 / 13卷 / 02期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

EGFR T790M; chemoproteomics; NT5DC1; bioimaging; target identification;

D O I：

10.1021/acsmedchemlett.1c00651

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：292 / 297

页数：6

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