PXD047093-1

PXD047093 is an original dataset announced via ProteomeXchange.

Title	Development of inhibitors, probes, and PROTAC provides a complete toolbox to study PARK7 in the living cell
Description	The innovation of combined chemical tools, such as small molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) for a specific target, not only advances clinical drug discovery but also provides a chemical toolbox to study the diverse biological perspective of targeted proteins. Here we report the development of such a chemical toolbox for the multifunctional human Parkinson disease protein 7 (PARK7/DJ-1) that has drawn attention as a candidate for drug discovery due to its involvement with Parkinson's disease and cancers. By combining structure-guided design, small library synthesis and high-throughput screening, we identified two compounds, JYQ-164 and JYQ-173, inhibiting PARK7 with high potency in vitro and in cell. These compounds covalently and selectively target its highly conserved and functionally essential residue, Cys106. Based on these compounds, we further developed two cell-permeable fluorescent probes, JYQ-192 and JYQ-196, with a SulfoCy5 dye to visualize PARK7 activity in living cells and a first-in-class PARK7 degrader JYQ-194 that selectively targets PARK7 to proteasomal degradation in human cells. Together, our study provides a valuable toolbox to advance the biology research of PARK7 in a cellular context and opens new opportunities for potential therapeutic application.
HostingRepository	PRIDE
AnnounceDate	2024-06-16
AnnouncementXML	Submission_2024-06-15_23:11:01.962.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rayman Tjokrodirijo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-20 03:36:13	ID requested
⏵ 1	2024-06-15 23:11:02	announced

10.1021/acs.jmedchem.3c02410;

Jia Y, Oyken M, Kim RQ, Tjokrodirijo RTN, de Ru AH, Janssen APA, Hacker SM, van Veelen PA, Geurink PP, Sapmaz A, Development of Inhibitors, Probes, and PROTAC Provides a Complete Toolbox to Study PARK7 in the Living Cell. J Med Chem, 67(10):7935-7953(2024) [pubmed]

submitter keyword: PARK7, small molecule inhibitors, PROTACs, activity-based probes

Peter A. van Veelen
contact affiliation	Head Proteomics Group, Leiden University Medical Center, Center for Proteomics and Metabolomics, PO Box 9600, Postal zone P1-Q, 2300 RC Leiden, The Netherlands
contact email	P.A.van_Veelen@lumc.nl
lab head
Rayman Tjokrodirijo
contact affiliation	Leiden University Medical Center, Proteomics group
contact email	R.T.N.Tjokrodirijo@lumc.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/06/PXD047093

PRIDE project URI

• PRIDE
  1. PXD047093
     1. Label: PRIDE project
     2. Name: Development of inhibitors, probes, and PROTAC provides a complete toolbox to study PARK7 in the living cell