Proteomics

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Development of inhibitors, probes, and PROTAC provides a complete toolbox to study PARK7 in the living cell


ABSTRACT: The innovation of combined chemical tools, such as small molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) for a specific target, not only advances clinical drug discovery but also provides a chemical toolbox to study the diverse biological perspective of targeted proteins. Here we report the development of such a chemical toolbox for the multifunctional human Parkinson disease protein 7 (PARK7/DJ-1) that has drawn attention as a candidate for drug discovery due to its involvement with Parkinson's disease and cancers. By combining structure-guided design, small library synthesis and high-throughput screening, we identified two compounds, JYQ-164 and JYQ-173, inhibiting PARK7 with high potency in vitro and in cell. These compounds covalently and selectively target its highly conserved and functionally essential residue, Cys106. Based on these compounds, we further developed two cell-permeable fluorescent probes, JYQ-192 and JYQ-196, with a SulfoCy5 dye to visualize PARK7 activity in living cells and a first-in-class PARK7 degrader JYQ-194 that selectively targets PARK7 to proteasomal degradation in human cells. Together, our study provides a valuable toolbox to advance the biology research of PARK7 in a cellular context and opens new opportunities for potential therapeutic application.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Rayman Tjokrodirijo  

LAB HEAD: Peter A. van Veelen

PROVIDER: PXD047093 | Pride | 2024-06-16

REPOSITORIES: Pride

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Development of Inhibitors, Probes, and PROTAC Provides a Complete Toolbox to Study PARK7 in the Living Cell.

Jia Yuqing Y   Oyken Merve M   Kim Robbert Q RQ   Tjokrodirijo Rayman T N RTN   de Ru Arnoud H AH   Janssen Antonius P A APA   Hacker Stephan M SM   van Veelen Peter A PA   Geurink Paul P PP   Sapmaz Aysegul A  

Journal of medicinal chemistry 20240507 10


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  ...[more]

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