TY - JOUR
T1 - Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1
AU - Tashiro, Shinya
AU - Caaveiro, Jose M.M.
AU - Nakakido, Makoto
AU - Tanabe, Aki
AU - Nagatoishi, Satoru
AU - Tamura, Yasushi
AU - Matsuda, Noriyuki
AU - Liu, Dali
AU - Hoang, Quyen Q.
AU - Tsumoto, Kouhei
N1 - Funding Information:
We thank the staff of the Photon Factory for excellent technical support. Access to beamlines BL5A, AR-NW12A, and AR-NE3A was granted by the Photon Factory Advisory Committee (Proposal Numbers 2011G574, 2012G191, 2013G738, 2014G190, and 2016G199). This work was supported by the Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K.T.), by JSPS KAKENHI-A grants 25249115 and 16H02420 (to K.T.), by a JSPS KAKENHI-C grant 15K06962 (to J.M.M.C.), by a MEXT KAKENHI grant JP18H02443 (to N.M), and by a Grant-in-Aid for JSPS Fellows (to S.T.).
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/9/21
Y1 - 2018/9/21
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.8b00701
DO - 10.1021/acschembio.8b00701
M3 - Article
C2 - 30063823
AN - SCOPUS:85053803428
SN - 1554-8929
VL - 13
SP - 2783
EP - 2793
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 9
ER -
