PXD006193-2

PXD006193 is an original dataset announced via ProteomeXchange.

Title	Discovery of dedicated EPHA2 inhibitors - Medicinal chemistry meets chemical proteomics
Description	The receptor tyrosine kinase EPHA2 has gained interest as therapeutical drug target in cancer and infectious diseases in the past years. However, EPHA2 research and EPHA2 based therapies have been hampered by the lack of selective small molecule EPHA2 inhibitors. We report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as lead structure. We designed hybrid structures of Dasatinib, CHEBI-513815, PD-173955 and a known EPHB4 inhibitor aiming at the exploitation of the ATP pocket entrance and the ribose pocket. Medicinal chemistry and inhibitor design was guided by a chemical proteomic approach allowing for early selectivity profiling of the newly synthesized inhibitor candidates. Additionally, protein crystallography delivered detailed insight into the molecular interactions that consitute structure-affinity-relationships. Finally, the anti-proliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we discovered a novel EPHA2 inhibitor candidate 4a comprising an improved selectivity profile while maintaining potency against EPHA2 and anti-cancer activity in SF-268 cells.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:05:10.953.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephanie Wilhelm
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2017-03-28 07:47:37	ID requested
1	2017-05-29 23:52:09	announced
⏵ 2	2024-10-22 04:05:13	announced	2024-10-22: Updated project metadata.

10.1002/cmdc.201700217;

Heinzlmeir S, Lohse J, Treiber T, Kudlinzki D, Linhard V, Gande SL, Sreeramulu S, Saxena K, Liu X, Wilhelm M, Schwalbe H, Kuster B, M, é, dard G, Chemoproteomics-Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors. ChemMedChem, 12(12):999-1011(2017) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: EPH receptor, drug discovery, selectivity profiling, inhibitors,chemical proteomics

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, Technische Universität München, Germany
contact email	kuster@tum.de
lab head
Stephanie Wilhelm
contact affiliation	Chair of Proteomics and Bioanalytics, Technische Universität München, Germany
contact email	stephanie.heinzlmeir@tum.de
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/2017/05/PXD006193

PRIDE project URI

• PRIDE
  1. PXD006193
     1. Label: PRIDE project
     2. Name: Discovery of dedicated EPHA2 inhibitors - Medicinal chemistry meets chemical proteomics