Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1

Shinya Tashiro, Jose M.M. Caaveiro, Makoto Nakakido, Aki Tanabe, Satoru Nagatoishi, Yasushi Tamura, Noriyuki Matsuda, Dali Liu, Quyen Q. Hoang, Kouhei Tsumoto

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2783-2793
Number of pages11
JournalACS Chemical Biology
Issue number9
Publication statusPublished - Sept 21 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine


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