Proteome-wide Identification of Off-Targets of a Potent EGFR L858R/T790M Mutant Inhibitor.
Peng LyuKaili JiangYuee ZhouJun HuYu ChangZhang ZhangMinhao HuangZhi-Min ZhangKe DingPiliang HaoLi-Gen LinZhengqiu LiPublished in: ACS medicinal chemistry letters (2022)
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.
Keyphrases
- epidermal growth factor receptor
- advanced non small cell lung cancer
- drug discovery
- tyrosine kinase
- small cell lung cancer
- dendritic cells
- quantum dots
- living cells
- single cell
- bioinformatics analysis
- mass spectrometry
- wild type
- anti inflammatory
- adverse drug
- drug induced
- stem cells
- emergency department
- risk assessment
- protein protein
- binding protein
- mesenchymal stem cells
- case control
- small molecule