We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A Suite of 'Minimalist' Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors.
- Authors
Pan, Sijun; Jang, Se ‐ Young; Wang, Danyang; Liew, Si Si; Li, Zhengqiu; Lee, Jun ‐ Seok; Yao, Shao Q.
- 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.
- Subjects
CELL imaging; PROTEOMICS; ALKYL group; SMALL molecules; DIAZIRINES
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 39, p11978
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201706076