2. Academic Validation
  3. Proteome-wide Identification of Off-Targets of a Potent EGFRL858R/T790M Mutant Inhibitor

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

  • ACS Med Chem Lett. 2022 Jan 19;13(2):292-297. doi: 10.1021/acsmedchemlett.1c00651.
Peng Lyu 1,  Kaili Jiang 2,  Yuee Zhou 2,  Jun Hu 2,  Yu Chang 2,  Zhang Zhang 2,  Minhao Huang 2,  Zhi-Min Zhang 2,  Ke Ding 2,  Piliang Hao 3,  Ligen Lin 1,  Zhengqiu Li 2
Affiliations

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.
PMID: 35178185 DOI: 10.1021/acsmedchemlett.1c00651
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 EGFRL858R/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.

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