PXD025257

PXD025257 is an original dataset announced via ProteomeXchange.

Title	Proteomics analysis with the WDR5 PROTACs
Description	Active gene transcription requires accessible chromatin. Post-translational modifications of histone proteins modulate accessibility to target genes, a process that is controlled by multiple chromatin modifying enzymes, remodelers and epigenetic reader proteins. Histone H3K4 methylation serves as hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMTs). For proper function of HMT activity, several adaptor proteins are required. One of these proteins is the WD-repeat containing protein 5 (WDR5) that acts as scaffolding component in HMT complexes and that has been associated with controlling transcription factors including MYC and long non-coding RNAs. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types has made WDR5 an attractive cancer drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might be an elegant way to target all oncogenic function. In this study, we present the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds. We show that linker nature and length are essential for successful degradation and strongly influences the degradation rate. In the presented datasets, we determined the intracellular degradation specificity of the WDR5 PROTACs (8g, 6, 17b, 14). We therefore treated MV4-11 cells with 8g and 17b, the corresponding ligands 6 and 14, or DMSO and quantified the induced degradation using a label free approach.
HostingRepository	PRIDE
AnnounceDate	2022-01-27
AnnouncementXML	Submission_2022-01-27_04:39:43.103.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nicola Berner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-08 03:03:03	ID requested
⏵ 1	2022-01-27 04:39:44	announced

D, ö, lle A, Adhikari B, Kr, ä, mer A, Weckesser J, Berner N, Berger LM, Diebold M, Szewczyk MM, Barsyte-Lovejoy D, Arrowsmith CH, Gebel J, L, ö, hr F, D, ö, tsch V, Eilers M, Heinzlmeir S, Kuster B, Sotriffer C, Wolf E, Knapp S, Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders. J Med Chem, 64(15):10682-10710(2021) [pubmed]

submitter keyword: PROTAC, Protein degrader, LC-MSMS, WDR5,

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
Nicola Berner
contact affiliation	German Cancer Consortium (DKTK), Germany Chair of Proteomics and Bioanalytics Technical University of Munich (TUM), Freising, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany
contact email	n.berner@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025257
     1. Label: PRIDE project
     2. Name: Proteomics analysis with the WDR5 PROTACs