期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 39, 页码 11816-11821出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201706076
关键词
affinity-based probes; bioorthogonal chemistry; epigenetics; live-cell imaging; photo-crosslinkers
资金
- National Medical Research Council, Singapore [CBRG/0038/2013]
- KIST [2E26632/2E26110, CAP-16-02-KIST]
- Bio & Medical Technology Development Program of the National Research Foundation from Ministry of Science, Korea [NRF-2016M3A9B6902060]
- National Research Foundation of Korea [2016M3A9B6902060] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Affinity-based probes (AfBPs) provide a powerful tool for large-scale chemoproteomic studies of drug-target interactions. The development of high-quality probes capable of recapitulating genuine drug-target engagement, however, could be challenging. Minimalist photo-crosslinkers, which contain an alkyl diazirine group and a chemically tractable tag, could alleviate such challenges, but few are currently available. Herein, we have developed new alkyl diazirine-containing photo-crosslinkers with different bioorthogonal tags. They were subsequently used to create a suite of AfBPs based on GW841819X (a small molecule inhibitor of BRD4). Through invitro and insitu studies under conditions that emulated native drug-target interactions, we have obtained better insights into how a tag might affect the probe's performance. Finally, SILAC-based chemoproteomic studies have led to the discovery of a novel off-target, APEX1. Further studies showed GW841819X binds to APEX1 and caused up-regulation of endogenous DNMT1 expression under normoxia conditions.
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