biostudies-literatureTashiro SNIGMS NIH HHS2783-2793https://www.ebi.ac.uk/biostudies/studies/S-EPMC6370461biostudies-literatureUnknown13(9)DJ-1 is a Parkinson's disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.ACS chemical biologyDiscovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1.PMC6370461R01 GM111639R01 GM115844Caaveiro JMMNagatoishi SHoang QQTamura YNakakido MTsumoto KMatsuda NLiu DTanabe ATashiro SfalseDiscovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1.DJ-1 is a Parkinson's disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.2018-01-01T00:00:00Z2018 Sep2021-02-20T01:04:48Z2019-03-26T22:54:23ZS-EPMC63704613006382310.1021/acschembio.8b00701