Tashiro, ShinyaCaaveiro, Jose M. M.Nakakido, MakotoTanabe, AkiNagatoishi, SatoruTamura, YasushiMatsuda, NoriyukiLiu, DaliHoang, Quyen Q.Tsumoto, Kouhei2018-09-192018-09-192018-07Tashiro, S., Caaveiro, J. M. M., Nakakido, M., Tanabe, A., Nagatoishi, S., Tamura, Y., … Tsumoto, K. (2018). Discovery and optimization of inhibitors of the Parkinson’s disease associated protein DJ-1. ACS Chemical Biology. https://doi.org/10.1021/acschembio.8b00701https://hdl.handle.net/1805/17352DJ-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.enPublisher PolicyParkinson's diseaseDJ-1inhibitorsArticle