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Jia, Yuqing; Oyken, Merve; Kim, Robbert Q.; Tjokrodirijo, Rayman T.N.; de Ru, Arnoud H.; Janssen, Antonius P. A.; Hacker, Stephan M.; van Veelen, Peter A.; Geurink, Paul P.; Sapmaz, Aysegul
Journal of medicinal chemistry, 2024-May-23, Volume: 67, Issue: 10Journal Article
The integration of diverse chemical tools like small-molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) advances clinical drug discovery and facilitates the exploration of various biological facets of targeted proteins. Here, we report the development of such a chemical toolbox for the human Parkinson disease protein 7 (PARK7/DJ-1) implicated in Parkinson’s disease and cancers. By combining structure-guided design, miniaturized library synthesis, and high-throughput screening, we identified two potent compounds, JYQ-164 and JYQ-173, inhibiting PARK7 in vitro and in cells by covalently and selectively targeting its critical residue, Cys106. Leveraging JYQ-173, we further developed a cell-permeable Bodipy probe, JYQ-196, for covalent labeling of PARK7 in living cells and a first-in-class PARK7 degrader JYQ-194 that selectively induces its proteasomal degradation in human cells. Our study provides a valuable toolbox to enhance the understanding of PARK7 biology in cellular contexts and opens new opportunities for therapeutic interventions.
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