Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 2, Pages 292-297Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00651
Keywords
EGFR T790M; chemoproteomics; NT5DC1; bioimaging; target identification
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Funding
- National Key R&D Program of China [2019YFC1711000]
- National Natural Science Foundation of China [82061128002, 82073715, 81973158]
- Science and Technology Program of Guangdong Province [2019B151502025]
- Science and Technology Development Fund, Macau SAR [-2020-2022]
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This study successfully identified the cellular off-target NT5DC1 of HP-1, a potential drug candidate for non-small cell lung cancer, through chemical proteomics and bioimaging studies.
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.
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