Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Proteomics Data for MDM2-targeting PROTACs in MDM2-Overexpressing HeLa Cells

ABSTRACT: Data files associated with the manuscript titled "Development of MDM2-targeting PROTAC for Advancing Bone Regeneration," which is currently under review. This manuscript introduces MDM2-targeting PROTACs specifically designed for applications in bone regeneration. We developed MDM2-PROTACs (CL144) that demonstrated potent degradation efficiency and a strong inductive effect on biomineralization. Proteomics analysis was conducted on HeLa cells overexpressing MDM2 to investigate the degradation selectivity of the compound. From the proteomics database search, we identified 8,353 proteins and observed the downregulation of several ubiquitin ligases and processing proteins, including USP29, USP48, RBX1, and ZNF598, in the HeLa cell experiment.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jun-Seok Lee

PROVIDER: MSV000097107 | MassIVE | Wed Feb 12 07:32:00 GMT 2025

REPOSITORIES: MassIVE

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Proteomics Data for MDM2-targeting PROTACs in hBMSCs

Project description:Data files associated with the manuscript titled "Development of MDM2-targeting PROTAC for Advancing Bone Regeneration," which is currently under review. This manuscript introduces MDM2-targeting PROTACs customized for application in bone regeneration. We developed MDM2-PROTACs (CL144) that demonstrated potent degradation efficiency and a strong inductive effect on biomineralization. Proteomics analysis was performed on human bone marrow-derived mesenchymal stem cells (hBMSCs) to investigate the degradation selectivity of the compound. Through proteomics database searches, we identified 6,388 proteins, including several differentially expressed proteins (DEPs), many of which are known to interact with MDM2 or play significant roles in the ubiquitin-proteasome system.

2025-02-12 | MSV000097106 | MassIVE

Development of MDM2-targeting PROTAC technology for advancing bone regeneration

Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.

2024-06-11 | GSE255297 | GEO

CRISPR/Cas9 and cDNA overexpression screens to identify transmembrane transporters involved in PROTAC sensitivity/resistance

Project description:Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. Here we used transporter-focused and genome-wide CRISPR/Cas9 as well as a barcoded solute carriere (SLC)-focused cDNA libraray to screen for transporters that are involved in the resistance or sensitivity to BET- and SLC9-targeting PROTACs.

2024-09-23 | GSE272433 | GEO

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

Project description:We evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of FDA-approved type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 JH1 tyrosine kinase domain enabled the rational design and optimization of Cereblon (CRBN)-directed JAK PROTACs utilizing multiple derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2-rearranged cell line and xenograft models of ALL.

| EGAS00001005180 | EGA

Proteolysis Targeting Chimeras With Reduced Off-targets

Project description:Proteolysis Targeting Chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a highthroughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogs to understand how functionalising different positions of the phthalimide ring, hydrogen bonding, steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed ALK oncoprotein-targeting PROTACs with enhanced potency and minimal offtarget degradation.

2023-12-20 | PXD046264 | Pride

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (RNA-Seq)

Project description:ENL, a stoichiometric component of the Super Elongation Complex (SEC) as well as the histone H3K79 methyltransferase DOT1L complex, is involved in the regulation of transcription elongation. Loss-of-function studies of ENL highlighted an essential role for its chromatin reader YEATS domain in the progression of acute leukemia, suggesting ENL as an attractive therapeutic target for leukemia therapy. Proteolysis targeting chimeras (PROTACs), a class of new therapeutic modalities, have the potential to degrade target proteinsthrough the ubiquitin-proteasome system. PROTACs have the potential to deliver robust therapeutic effects at low doses and infrequent dosing regimens with less side-effects. Here, we designed and synthesized a serial of ENL PROTACs. Through screening by ENL degradation in human leukemia cells, we identified MS47 as a potent ENL PROTAC. MS47 efficiently and specifically degrades ENL in a concentration-dependent and time dependent manner. In line with the mechanism of action of PROTACs, proteasome inhibitors can block ENL degradation mediated by MS47. MS47 suppresses survival and growth of a panel of acute leukemia cells, and efficiently suppresses the expression of ENL target genes, including Hoxa9, Meis1, Myb and Myc. In disseminated xenograft model, MS47 significantly benefits mouse survival, inhibits leukemia cell growth in vivo. No obvious toxic effect shown in toxicity test in vivo. Modest changes occurred on normal hematopoiesis. Together, our study developed a potent ENL PROTAC for leukemia treatment.

2024-09-13 | GSE245926 | GEO

A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (ChIP-Seq)

2024-09-13 | GSE245925 | GEO

Transcriptome analysis PIM kinase inhibition vs degradation

Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

2023-12-04 | GSE237256 | GEO

Enhancement of ubiquitination-dependent mitophagy by unconventionally-acting PROTACs

Project description:Enhancing mitophagy, a naturally-occurring cellular process for elimination of damaged mitochondria, holds great promise for the intervention of many human diseases. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce ubiquitination and subsequent proteasome-mediated degradation of a target protein through simultaneously binding to the target protein and an E3 ubiquitin ligase. However, the narrow cavity of the proteasome prevents the degradation of mitochondria. Here we show that the E3 ubiquitin ligase MAP3K1, when recruited to the outer mitochondria membrane (OMM) protein TSPO by our PROTAC-designed molecules (termed “mitophagy-enhancing chimeras”, or MECs), induced extensive K63 ubiquitination of TSPO and other OMM proteins, reminiscent of the PINK1-activated Parkin, without triggering proteasome-mediated degradation of TSPO. Aided by NBR1 and Nur77, this increased K63 ubiquitination of OMM proteins triggered mitophagy exclusively for damaged mitochondria, leading to improved mitochondria function and diminished cellular ROS. With the capability to enhance mitophagy at low nanomolar concentrations, MECs effectively inhibited NLRP3 inflammasome activation, abrogated acetaminophen-induced acute liver injury and mitigated high-fat diet-induced obesity in mice. Our work provided a proof-of-concept for developing unconventionally-acting PROTACs to achieve degradation of damaged mitochondria and possibly other organelles.

2024-02-08 | GSE255354 | GEO

Quantitative proteomic analysis of targeted degradation following Pep-TAC treatment

Project description:Quantitative proteomic analysis raw data for the manuscript entitled “A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy”.

2025-01-22 | PXD060051 |

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