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A Suite of 'Minimalist' Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors.
- Source :
-
Angewandte Chemie International Edition . 9/18/2017, Vol. 56 Issue 39, p11816-11821. 6p. - Publication Year :
- 2017
-
Abstract
- Affinity-based probes (A fBPs) 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 A fBPs based on GW841819X (a small molecule inhibitor of BRD4). Through in vitro and in situ 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14337851
- Volume :
- 56
- Issue :
- 39
- Database :
- Academic Search Index
- Journal :
- Angewandte Chemie International Edition
- Publication Type :
- Academic Journal
- Accession number :
- 125188609
- Full Text :
- https://doi.org/10.1002/anie.201706076