Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of an Exquisitely Selective WDR5 Chemical Probe Accelerated by a High-Quality DEL-ML Hit

ABSTRACT: A chemoproteomics experiment was performed to investigate the selectivity of the WDR5 targeting compound LH168. Therefore, a biotinylated adduct of LH168, namely LH205, was used to enrich potential target proteins of LH168. The addition of LH168 in excess competed only the interaction with LH168, demonstrating a proteome wide selectivity of LH168 for WDR5.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Matthias Gstaiger

LAB HEAD: Matthias Gstaiger

PROVIDER: PXD063455 | Pride | 2025-09-15

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20240827_065417_Ex20240820_WDR5.sne	Other
	20240827_135155_Ex20240820_WDR5_Report.tsv	Tabular
	240822_LU1_sabkell_Ex20240820_10_DDA.raw	Raw
	240822_LU1_sabkell_Ex20240820_10_DIA.raw	Raw
	240822_LU1_sabkell_Ex20240820_10_DIA_2.raw	Raw

Items per page:

1 - 5 of 37

Publications

Discovery of an exquisitely selective WDR5 chemical probe accelerated by a high-quality DEL-ML Hit.

Hoffmann Lasse L Lenz Christopher C Farges Frederic F Kimani Serah W SW Dopfer Johannes J Keller Sabrina S Schwalm Martin Peter MP Holzmann Hanna H Kraemer Andreas A Dong Aiping A Li Fengling F Chau Irene I Halabelian Levon L Gstaiger Matthias M Müller Susanne S Knapp Stefan S Němec Václav V

RSC chemical biology 20250717

Herein we present the rapid development of LH168, a potent and highly selective chemical probe for WDR5, streamlined by utilizing a DEL-ML (DNA encoded library-machine learning) hit as the chemical starting point. LH168 was comprehensively characterized in bioassays and demonstrated potent <i>in cellulo</i> target engagement at the WIN-site pocket of WDR5, with an EC<sub>50</sub> of approximately 10 nM, a long residence time, and exceptional proteome-wide selectivity for WDR5. In addition, we pr ...[more]

PMID: 40927425

Similar Datasets

Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors

Project description:SM311 is a covalent LIMK1 inhibitor. To verify the specificity of SM311 towards LIMK1, a chemoproteomic competition experiment was set up with a biotin adduct of SM311, namely SM429. This adduct was immobilised on Streptactin beads and used to enrich proteins binding to SM429. Preincubation with an excess of SM311 was used as control to outcompete and block the binding of SM429. In the competition setup we show that LIMK1 is depleted if SM311 is added in excess but also identified two additional kinase off-targets that required further profiling.

2025-08-04 | PXD063179 | Pride

WDR5 protein interactions at the WIN-site

Project description:The WIN site of WDR5 is a druggable pocket that impairs WDR5 protein function and carries therapeutic potential for treating cancer. This study evaluates the protein interactions affected by small molecule blockade of this surface on WDR5. Inhibited and uninhibited WDR5-containing complexes from HEK293 cells were quantitatively compared by SILAC-based proteomics. Of the high confidence proteins affected by this inhibition, one protein, PDPK1, was investigated further by mass spectrometry for identification of post translational modifications that could influence binding to WDR5.

2021-01-25 | PXD019209 | Pride

A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylationon Histone H3 and in Prostate Cancer

Project description:Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target genes activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P and this interaction facilitates the recruitment of the SET1/MLL complex and subsequent H3K4 trimethylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a six-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knock-down or chemical inhibition severely blocks WDR5 association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation, and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and a major driver of androgen-dependent prostate cancer cell proliferation. Identification of Histone 3 threonine 11 phosphorylation (H3T11P) marks and WDR5 binding sites in LNCaP cells treated with R1881 ligand (androgen) or solvent control.

2014-07-01 | E-GEOD-55279 | biostudies-arrayexpress

Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network (2)

Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. It remains unclear whether interactions. Here we show that a core member of the Set/MLL complex, WDrepeat protein-5 (Wdr5), is a novel regulator of self-renewal and partners with Oct4 to maintain an intact transcriptional network and for efficient formation of induced pluripotent stem (iPS) cells. Moreover, we provide evidence that Oct4 interacts with chromatin components and is indispensible for epigenetic regulation. These findings suggest an integrated transcriptional and epigenetic model, mediated through Wdr5, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Differential gene expressions upon down-regulation of Wdr5 was analysed by comparing Wdr5R4 –dox (triplicate) and LucR +dox (duplicate) RNA samples Gene expression changes upon down-regulation of Oct4 was analysed by comparing Oct4 shRNA (duplicate) and GFP shRNA (duplicate) after 4day transfection Wdr5: 5 samples are analyzed: Luciferase (Luc, 2 replicates) and Wdr5 with no dox (minusDox, 3 replicates) Oct4-GFP: 4 samples are analyzed: Oct4 shRNA (Oct4, 2 replicates) and GFP shRNA (GFP, 2 replicates)

2011-04-08 | E-GEOD-19588 | biostudies-arrayexpress

Multiplexed interactome analysis reveals the molecular architecture of the human prefoldin network

Project description:The majority of proteins are organized in protein complexes. Protein complexes represent an important cellular organizational layer, which regulate and catalyze most of the cellular processes. Within the field of proteomics several techniques such as Affinity Purification (AP) and co-fractionation (co-Frac) coupled to mass spectrometry (MS) were developed in order to study protein complexes. Our approach, deep interactome profiling coupled to MS (DIP-MS), is a combination of the benefits of these approaches by combining the selectivity of AP-MS together with a blue native-page size-based fractionation, in order to deconvolute the co-purified complexes, in which the bait is a constitutive subunit. To ensure high-quality quantitation along the fractionation gradient, and to keep data acquisition time limited, we developed a high-throughput (HT) sample preparation method and high-throughput data independent acquisition (DIA) method, enabling us to acquire almost one co-Frac gradient per day. Additionally, a tailored machine learning approach was devised – protein-protein interaction prophet (PPIprophet) which enabled the scoring of the co-elution proteins to retrieve PPIs respectively protein complexes. The method was employed to depict the complex modularity within the prefoldin and prefoldin-like protein complexes, allowing us to I) describe protein complex isoforms, II) derive stoichiometries and abundance distributions of co-purified complexes and III) identify reported and new client proteins and client complexes of the PAQosome, a multi-subunit co-chaperone complex, necessary for the stabilization and formation of multiple complexes such as the RNA polymerases (RNA Pol I, RNA Pol II, RNA Pol III). This study thereby demonstrates the applicability of our method and shows it strength and sensitivity by depicting the prefoldin complexes within only a single experiment.

2024-03-11 | PXD035032 | Pride

Proteomics analysis with the WDR5 PROTACs

Project 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.

2022-01-27 | PXD025257 | Pride

Unannotated microprotein EMBOW switches WDR5 between epigenetic and mitotic roles during cell cycle

Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.

2023-09-19 | PXD036699 | Pride

Interactome of the long non-protein coding RNA (lncRNA) D4Z4 binding element-transcript (DBE-T)

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an inherited progressive neuromuscular disorder that afflicts both children and adults regardless of gender. FSHD is caused by aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.

2023-04-11 | PXD036038 | Pride

Altered expression of genes in WDR5 knockdown

Project description:WDR5 (WD repeat domain 5) plays an important role in the epigenetic regulation of gene transcription, involing in regulation of embryonic stem cell and cancer cell.Bladder cancer is one of the most common cancers that cause approximately 150,000 deaths per year worldwide.The goal of this study is to identify the target genes of WDR5 in bladder cancer.Our results inditcate that the genes regulated by WDR5 involved in a variety of biological functions, such as proliferation and anti-apoptosis. Bladder cancer cell line UM-UC-3 was transfected with the contol siRNA or two different WDR5 siRNA for 48h. The RNA of the transfected cells was extracted and hybridized on Affymetrix microarrays. We indentified the putative target genes of WDR5 in both WDR5 siRNA by comparing the diferent expressed genes among control, si-WDR5-2 and si-WDR5-3. We futher validated the data of microarray in UM-UC-3 and T24 by RT-qPCR and Western bloting.

2015-02-09 | E-GEOD-59132 | biostudies-arrayexpress

The histone H3 lysine 4 presenter WDR5 induces N-Myc target gene transcription and promotes neuroblastoma [gene expression]

Project description:WDR5 is an important co-factor for N-Myc-regulated transcriptional activation and tumorigenesis We analysed whether WDR5 siRNAs modulate gene expression Neuroblastoma BE(2)-C cells were treated with control siRNA, WDR5 siRNA-1, and WDR5 siRNA-2 for 40 hours, and subjected to differential gene expression studies with Affymetrix microarrays.

2015-12-31 | E-GEOD-69861 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data