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MAGL Targeted PROTAC Degrader Simultaneously Enhances P53 for Synergistic Treatment of Glioblastoma Stem Cell

ABSTRACT: This study focuses on the protein degradation effects of the MAGL inhibitor JZL184 and the newly synthesized MAGL-PROTAC on MAGL.

ORGANISM(S): Homo Sapiens

SUBMITTER: JinLong Yin

PROVIDER: PXD058506 | iProX | Mon Dec 02 00:00:00 GMT 2024

REPOSITORIES: iProX

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MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell.

Yuan Zheng Z Guo Meixia M Zhang Yue Y Deng Yilin Y Sun Biao B Hou Yaning Y Wang Xin X Jin Xiong X Liu Yang Y Shi Bingyang B Yin Jinlong J

Cell death discovery 20250320 1

Glioblastoma (GBM) stands as the most fatal brain tumor due to limited therapeutic options and high rates of drug resistance. Current surgical and pharmacological interventions usually fail to eradicate the aggressive GBM stem cells (GSCs), which leads to the deadly GBM occurrence. Although proteolysis-targeting chimeras (PROTACs) are prosperous in drug development for tumors, their application in GBM, particularly for GSC-sensitive drug candidates remains in its nascent stages. In this regard, ...[more]

PMID: 40113745

Similar Datasets

MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell.

Project description:Glioblastoma (GBM) stands as the most fatal brain tumor due to limited therapeutic options and high rates of drug resistance. Current surgical and pharmacological interventions usually fail to eradicate the aggressive GBM stem cells (GSCs), which leads to the deadly GBM occurrence. Although proteolysis-targeting chimeras (PROTACs) are prosperous in drug development for tumors, their application in GBM, particularly for GSC-sensitive drug candidates remains in its nascent stages. In this regard, we designed a monoacylglycerol lipase (MAGL) targeting PROTAC, where MAGL was identified as a novel target for GSCs in our previous study. The MAGL inhibitor JZL184 was redesigned by leveraging computational chemistry analysis, and an active unit was engaged for conjugation. E3 ligand for MAGL targeted warhead conjugation was screened with bioinformatics analyses, which revealed heightened activity of the E3 ligase MDM2 in GBM, a classic negative regulator of the tumor suppressor P53, which correlates with patient prognosis. Then the PROTAC was conjugated with JZL184 analog and the MDM2 inhibitor Nutlin-3 analog. Experimental results validated that the designed JN-PROTAC effectively induced MAGL targeted degradation and concomitantly enhanced P53 activation via MDM2 inhibition and is capable of inhibiting the progression of patient-derived GSCs in vivo. This work presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM.

| S-EPMC11926070 | biostudies-literature

Drugtamer-PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy.

Project description:Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer-PROTAC conjugation approach is developed to enhance tumor targeting and antitumor potency. Specifically, a smart prodrug is designed by conjugating "drugtamer" to a nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using a tumor microenvironment responsible linker. The "drugtamer" consists of fluorouridine nucleotide and DNA-like oligomer. Compared to NAMPT PROTAC and the combination of PROTAC + fluorouracil, the designed prodrug AS-2F-NP demonstrates superior tumor targeting, efficient cellular uptake, improved in vivo potency and reduced side effects. This study provides a promising strategy for the precise delivery of PROTAC and synergistic antitumor agents.

| S-EPMC11220662 | biostudies-literature

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

Project description:The RNA decapping scavenger, DcpS, has recently been identified as a dependency in acute myeloid leukemia. The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by modulation of DcpS. Considering this strong dependence of AML cell lines on DcpS, we wanted to explore PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, the first PROTAC capable of degrading an mRNA-decapping enzyme. JCS-1 non-covalently binds DcpS with an RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 will serve as a chemical biology tool to interrogate DcpS function in different cellular contexts and may be an applicable strategy for the treatment of AML and other DcpS-dependent genetic disorders.

2022-07-08 | GSE207500 | GEO

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

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.

Project description:Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC. SIGNIFICANCE: These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.

| S-EPMC6318015 | biostudies-literature

Functional characterization of a PROTAC directed against BRAFV600E

Project description:The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation, and survival enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAFV600E have shown great efficacy in the clinic but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC termed P4B displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAFV600E cell lines. In addition, P4B displayed utility in two cell lines harboring alternate BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a rationale for optimizing the drug-like properties of P4B to enable proof of concept studies in vivo.

2020-05-25 | GSE148500 | GEO

AP-PROTAC-2: a Photoswitchable multi-kinase PROTAC

Project description:Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

2022-09-14 | PXD036224 | Pride

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

Project description:Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

| PRJNA855935 | ENA

Gene expression in Mon-Mac-6 cells treated with METTL3 PROTAC, WD6305

Project description:We developed a new METTL3 PROTAC, WD6305, which, unlike inhibitors, can reduce the expression of METTL3 protein. Here, we tested the gene expression after dosing by RNA-seq.

2023-11-29 | GSE234985 | GEO

The effect of PROTAC-mediated depletion of TAF1 on gene expression

Project description:The goal of this experiment was to determine the change in gene expression after transient depletion of the TAF1 transcription factor (aka TFII-250) using a PROTAC molecule (ZS3-046) containing GNE371 as TAF1 ligand and pomalidomide as CRBN ligand.

2025-04-01 | GSE289670 | GEO

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