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Showing 1 to 20 of 22 for “"PROTACs"”.
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Synthesis of Non-Steroidal Estrogen Receptor Proteolysis Targeting Chimeric Molecules (Protacs)
To make the PROTAC design more useful, a small molecule E3 ligase peptide mimic is desirable. The HIF-1alpha E3 ligase destruction sequence utilized in the PROTAC design requires a hydroxylated proline residue for recognition by the VCB E3 ligase. The synthesis of a tetrahydrofuran-based …
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Proteolysis targeting chimeras for the directed ubiquitination of the androgen receptor
Proteolysis targeting chimeras (PROTACs) are an emerging field of therapeutics and promising potential drug candidates. PROTACs consist of a target protein binder connected via a linker to an E3 ligase binder. PROTACs hijack the ubiquitin proteasome system to degrade the target protein in a …
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The Design, Synthesis and in vitro Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Degradation of Protein Arginine Methyltransferase 1
… using a PROTAC may be superior to inhibition as PROTACs can act catalytically at a low dose. PROTACs can also exhibit high selectivity and cause a more pronounced functional outcome compared to inhibition. In this thesis, PRMT1 is explored as a target protein for PROTAC-induced degradation. The …
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Novel Proteolysis Targeting Chimeras for the targeted degradation of the protein kinase CK2
… a lack of prolonged suppression of CK2 activity. PROTACs (Proteolysis Targeting Chimeras) represent a novel therapeutic strategy that can induce target degradation through the 26S proteasome, offering potential advantages in potency, selectivity, and prolonged biological activity. The aim of this …
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Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites
… the use of Proteolysis-targeting chimeras (PROTACs) that can induce the degradation of a target protein via the cells ubiquitin-proteasome system rather than inhibiting it. Ideally, for PROTACs to be effective in malaria research, they should bind to essential proteins, such as epigenetic …
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Cellular Determinants Of AURKA Degradation By Small Molecule Proteolysis-Targeting Chimeras
… development of proteolysis-targeting chimeras (PROTACs) has enhanced the field of ubiquitin signalling through advancing therapeutic targeted protein degradation (TPD) strategies and generating tools to explore the ubiquitin landscape. However, the cellular factors that modulate PROTAC activity, …
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Using Heterogeneous Information Sources for Understanding and Predicting Biological Effects of Compounds
… such as PROteolysis TArgeting Chimeras (PROTACs). In the first chapter, “Probabilistic Random Forest improves bioactivity predictions close to the classification threshold by taking into account experimental uncertainty”, a novel algorithm was evaluated and benchmarked. A limiting factor …
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Induced Degradation of G-Protein-Coupled Receptors Through Proteolysis Targeting Chimeras
… methods include proteolysis targeting chimeras (PROTACs), which are heterobifunctional molecules where one end has a ligand for the protein-of-interest (POI), and the other end has an E3 ligase recruiting ligand. PROTACs take advantage of the ubiquitin-proteasome system (UPS) by forcing a POI in …
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Chemical Tools for Exploring Metabolite Interactions with Nuclear Receptors and Beyond
… combined use of proteolysis-targeting chimeras (PROTACs) and chemical proteomics in target deconvolution studies. We describe the design and synthesis of PROTACs that recruit putative E3 ligases. Overall, the projects described herein underline the utility of chemical tools such as …
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Developing Targeted Therapies for T-cell Acute Lymphoblastic Leukemia
… a set of proteolysis targeting chimeras (PROTACs) to degrade LCK in T-ALL. Western blotting was used to measure the extent of degradation of LCK and other target proteins by PROTACs. Cell viability assays were performed in leukemia cell lines and PDX cells to determine cytotoxicity of …
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Broad-spectrum antivirals against coronavirus using natural products and drug repurposing strategies
… strategies through the repurposing of PROTACs (Proteolysis-Targeting Chimeras). Originally developed for oncology, these bifunctional molecules were assessed for their ability to degrade key host proteins exploited by coronaviruses during replication and entry. Select PROTACs targeting …
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Small-molecule approaches to interrogate the druggability of the VHL E3 Cullin RING Ubiquitin Ligase
… bifunctional degrader molecules (also known as PROTACs) to hijack VHL activity to induce targeted protein degradation. This work aimed to develop novel small molecules that target two different binding sites on the surface of VHL: 1) the hydroxyproline recognition site of HIF-α; and 2) a newly …
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Developing Computational Methods in Proximity Pharmacology for Enzyme Discovery, PROTAC Screening, and Conformational Space Exploration
… called Proteolysis Targeting Chimeras (PROTACs), have shown clinical promise, with two currently in Phase 3 trials. Beyond degradation, the field of proximity pharmacology explores the recruitment of other enzymes, such as kinases, to induce post-translational modifications. While …
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Targeting Transcription Factors in Neuroblastoma: Development of Aurora Kinase A/N-Myc Degraders and ID2 Chemical Probes
… hydrophilic chemical linkers in Aurora-A/N-Myc PROTACs to improve the physicochemical properties of 2.3. Inhibitor of DNA-binding 2 (ID2) has been found to be critical for tumorigenesis and its expression is strongly predictive of poor prognosis for neuroblastoma patients. However, validation of …
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Modulation of BAZ2 Proteins as a Potential Therapeutic Strategy in Cancer and Neurological Disorders
… BAZ2A degraders was accomplished, categorizing PROTACs according to their capability to recruit CRBN or VHL E3 ligases. Preliminary experiments revealed that VHL-based degraders featuring longer linkers promoted BAZ2A degradation, confirming the PROTAC potential in successfully mediating POI …
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Multimethodological approaches to tackle glycogen: therapeutic and modelling opportunities in Lafora disease
… sharpen the design of PTG-specific inhibitors or PROTACs. On the other hand, a forward chemogenomic approach has been explored to set up a robust and unbiased HCS strategy. A phenotypic assay tailored to detect glycogen with GST-tagged PTG-CBM21 domain has been validated, showing the advantage of …
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CHEMICAL APPROACHES TOWARD NEW PERSPECTIVES IN DRUG DISCOVERY: NATURAL PRODUCTS AND BIOACTIVE HITS AS AN INSPIRATION
… the emerging proteolysis-targeting chimeras (PROTACs), to inspire the design of innovative molecular architectures that can selectively degrade target proteins. The strategic incorporation of bioactive natural compounds into these bivalent frameworks not only enhances target specificity, but …
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Construction and Biological Characterisation of Custom Engineered Protein Degradation Tools.
Event-driven pharmacology is a new paradigm in disease treatment for a wide range of diseases, including cancer, that have failed by traditional occupancy-driven pharmacology. One target that has been resistant to conventional inhibition approaches is Aurora A (AurA). Degradation rather than …
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RNA Therapeutics for Fibrolamellar Hepatocellular Carcinoma
… antisense oligonucleotides, siRNAs, and possibly PROTACS for targeted intervention. This work establishes a foundation for the development of precision therapies against FLC, highlighting the importance of the DNAJB1::PRKACA fusion kinase as a therapeutic target and serving as a model for …
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Harnessing the Anaphase-Promoting Complex for Targeted Protein Degradation
Targeted protein degradation (TPD) is rapidly becoming a prevalent modality of therapeutics development due to its event-driven pharmacology that overcomes some major limitations of conventional small molecule inhibitors. One of the paradigms of TPD involves co-opting components of the …
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