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

  • J Med Chem. 2024 May 23;67(10):7935-7953. doi: 10.1021/acs.jmedchem.3c02410.
Yuqing Jia  1  2 ,  Merve Oyken  1 ,  Robbert Q Kim  1 ,  Rayman T N Tjokrodirijo  3 ,  Arnoud H de Ru  3 ,  Antonius P A Janssen  4 ,  Stephan M Hacker  4 ,  Peter A van Veelen  3 ,  Paul P Geurink  1 ,  Aysegul Sapmaz  1
Affiliations
  • 1. Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, The Netherlands.
  • 2. Laboratory for Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 3, Zürich CH-8093, Switzerland.
  • 3. Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
  • 4. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
PMID: 38713163 DOI: 10.1021/acs.jmedchem.3c02410
Abstract

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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