PXD040391

PXD040391 is an original dataset announced via ProteomeXchange.

Title	Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma
Description	Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to both its catalytic functions during mitosis and its kinase-independent functions, including stabilization of the key oncoprotein MYCN. We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. PROTAC SK2188 induces the most potent AURKA degradation (DC50,24h 3.9 nM, Dmax,24h 89%) and shows an excellent binding and degradation selectivity profile. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis. Moreover, SK2188 significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:35:06.650.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD040391
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Teresa Mendes Maia
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-24 06:19:19	ID requested
1	2023-02-27 05:16:21	announced
⏵ 2	2023-11-14 08:35:07	announced	2023-11-14: Updated project metadata.

10.6019/PXD040391;

Rishfi M, Krols S, Martens F, Bekaert SL, Sanders E, Eggermont A, De Vloed F, Goulding JR, Risseeuw M, Molenaar J, De Wilde B, Van Calenbergh S, Durinck K, Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma. Eur J Med Chem, 247():115033(2023) [pubmed]

submitter keyword: AURKA

MYCN

Neuroblastoma

PROTAC

Targeted protein degradation

Kaat Durinck
contact affiliation	Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
contact email	Kaat.Durinck@UGent.be
lab head
Teresa Mendes Maia
contact affiliation	VIB Proteomics Core
contact email	teresa.maia@vib-ugent.be
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/2023/02/PXD040391

PRIDE project URI

• PRIDE
  1. PXD040391
     1. Label: PRIDE project
     2. Name: Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma