Chemical Toolkit for PARK7: Potent, Selective, and High-Throughput

• Published in: Journal of medicinal chemistry Vol. 65; no. 19; pp. 13288 - 13304
• Main Authors: Jia, Yuqing, Kim, Robbert Q., Kooij, Raymond, Ovaa, Huib, Sapmaz, Aysegul, Geurink, Paul P.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2022; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; HUMAN DJ-1; ASSAY; INDUCED APOPTOSIS; RESISTANCE; INHIBITORS; MUTATIONS; IDENTIFICATION; DEGLYCASE; METHYLGLYOXAL; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01113

The multifunctional human Parkinson’s disease protein 7 (PARK7/DJ1) is an attractive therapeutic target due to its link with early-onset Parkinson’s disease, upregulation in various cancers, and contribution to chemoresistance. However, only a few compounds have been identified to bind PARK7 due to the lack of a dedicated chemical toolbox. We report the creation of such a toolbox and showcase the application of each of its components. The selective PARK7 submicromolar inhibitor with a cyanimide reactive group covalently modifies the active site Cys106. Installment of different dyes onto the inhibitor delivered two PARK7 probes. The Rhodamine110 probe provides a high-throughput screening compatible FP assay, showcased by screening a compound library (8000 molecules). The SulfoCy5-equipped probe is a valuable tool to assess the effect of PARK7 inhibitors in a cell lysate. Our work creates new possibilities to explore PARK7 function in a physiologically relevant setting and develop new and improved PARK7 inhibitors.