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

Abstract

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.

Novel Insights into PARK7 (DJ-1), a Potential Anti-Cancer Therapeutic Target, and Implications for Cancer Progression

“…Potent 1H-indole-2,3-dione derivatives have recently developed as a compound inactivating the critical Cys106 residue of PARK7 by binding potent PARK7 inhibitors to a conspicuous pocket (Cys106) of PARK7. The maximal affinity and inhibitory potency (IC 50 ) of PARK7 inhibitors were 100 and 300 nM, respectively [137]. The continuous studies using these PARK7 inhibitors may need more evaluations for the therapeutic application of cancers and neurodegenerative diseases.…”

Discovery of Novel Druggable Sites on Zika Virus NS3 Helicase Using X-ray Crystallography-Based Fragment Screening

“…Sulfhydryl groups of cysteine residues are generally known to engage in a range of interactions in native proteins [ 40 ]. With respect to small molecule ligands, covalent binding to cysteines is often a desired design feature, as this leads to prolonged target engagement and hence a sustained drug action [ 41 , 42 ].…”

Knockdown of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition

“…4 Recently, several compounds were identified as potent inhibitors of DJ-1 to inactivate the critical Cys106 residue by using biophysical methodologies and X-ray crystallography. 19 All of these RNAi and small molecular inhibitors may facilitate clinical application of targeting DJ-1 in the future.…”