PXD045438

PXD045438 is an original dataset announced via ProteomeXchange.

Title	Discovery and Functional Characterization of a Potent, Selective and Metabolically Stable PROTAC Degrader of the Protein Kinases DYRK1A and DYRK1B
Description	Alternative to enzyme inhibition, small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development and adaptive immune homeostasis. Here we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP- competitive DYRK1 inhibitor with ligands for the E3 ubiquitin ligase component Cereblon (CRBN) to induce ubiquitinylation and subsequent proteasomal degradation of DYRK1A and DYRK1B. The lead compound (DYR684) promoted fast, efficient, potent and selective degradation of endogenous DYRK1A in cell-based assays. Although DYR684 was also active against DYRK1B, we observed that an enzymatically inactive splicing variant of DYRK1B (p65) was resistant to degradation. Com- pared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of down- stream signaling. Moreover, DYR684 sensitized SH-SY5Y neuroblastoma cells to the cytotoxic effects of the anticancer drug cisplatin. Collectively, our results identify DYRK1A and DYRK1B as viable targets for PROTAC-mediated degradation and qual- ify DYR684 as a suitable chemical probe for functional studies of the catalytically active DYRK1A and DYRK1B variants.
HostingRepository	PRIDE
AnnounceDate	2024-09-30
AnnouncementXML	Submission_2024-09-30_08:54:49.621.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sebastian Kallabis
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-18 03:18:28	ID requested
⏵ 1	2024-09-30 08:54:50	announced

10.1021/ACS.JMEDCHEM.4C01130;

submitter keyword: DYRK1, Cereblon, PROTAC

Walter Becker
contact affiliation	Institute of Pharmacology and Toxicology RWTH Aachen University Wendlingweg 2 52074 Aachen, Germany
contact email	wbecker@ukaachen.de
lab head
Sebastian Kallabis
contact affiliation	Department for Systems Immunology & Proteomics Institute of Innate Immunity University Hospital Bonn Venusberg - Campus 1 53127 Bonn Germany
contact email	kallabis@uni-bonn.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045438
     1. Label: PRIDE project
     2. Name: Discovery and Functional Characterization of a Potent, Selective and Metabolically Stable PROTAC Degrader of the Protein Kinases DYRK1A and DYRK1B