PXD019585-1

PXD019585 is an original dataset announced via ProteomeXchange.

Title	Proteomics analysis with the Aurora-A PROTAC, JB170
Description	The mitotic kinase Aurora-A is essential for cell cycle progression and considered a priority cancer target. Dozens of ongoing clinical trials are testing the anti-cancer potential of Aurora-A kinase inhibitors. While the catalytic activity of Aurora-A is essential for its function during mitosis, a growing body of evidence indicates an additional non-catalytic function, which is difficult to target by kinase inhibitors. We therefor developed a series of degrader molecules by connecting a kinase inhibitor of Aurora-A to the Cereblon-binding molecule thalidomide. One degrader, JB170, induced the rapid degradation of Aurora-A. We were able to show that JB170 mediated depletion is highly specific for Aurora-A, as degrader mediated complex formation is supported by cooperative binding between Cereblon and Aurora-A. Strikingly, JB-170 mediated depletion caused a strong S-phase arrest, which is not the cell cycle effect observed as a result of Aurora-A kinase inhibition, supporting an important non-catalytic role of Aurora-A during DNA replication. Finally, depletion of Aurora-A resulted in strong induction of apoptosis in various cancer cell lines. The tool compound JB170 presents a versatile starting point for developing new therapeutic drugs to counter Aurora-A function in cancer. In the presented datasets, we determined i) the binding selectivity profile of the Aurora-A PROTAC (JB170) using Kinobeads affinity matrix and ii) its intracellular degradation specificity. We therefore treated IMR5 cells with JB170, the inactive version JB211, or Alisertib and quantified the induced degradation using tandem mass tags.
HostingRepository	PRIDE
AnnounceDate	2020-09-28
AnnouncementXML	Submission_2020-09-28_06:26:35.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephanie Heinzlmeir
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-04 06:31:07	ID requested
⏵ 1	2020-09-28 06:26:35	announced
2	2024-10-22 05:12:51	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Proteomics analysis with the Aurora-A PROTAC, JB170

Prof. Dr. Bernhard Kuster
contact affiliation	Technical University of Munich Chair of Proteomics and Bioanalytics Emil-Erlenmeyer-Forum 5 85354 Freising, Germany
contact email	kuster@tum.de
lab head
Stephanie Heinzlmeir
contact affiliation	Chair of Proteomics and Bioanalytics, Technische Universität München, Germany
contact email	stephanie.heinzlmeir@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019585
     1. Label: PRIDE project
     2. Name: Proteomics analysis with the Aurora-A PROTAC, JB170