A Suite of "Minimalist" Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors

Title
A Suite of "Minimalist" Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors
Authors
이준석장세영Sijun PanDanyang WangSi Si LiewZhengqiu LiShao Q. Yao
Keywords
affinity-based probes; bioorthogonal chemistry; epigenetics; live-cell imaging; photo-crosslinkers
Issue Date
2017-09
Publisher
Angewandte Chemie international edition
Citation
VOL 56-11821
Abstract
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 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 probeQs 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.
URI
http://pubs.kist.re.kr/handle/201004/66176
ISSN
1433-7851
Appears in Collections:
KIST Publication > Article
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