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

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.