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Showing 1 to 20 of 27 for “"PROTAC"”.
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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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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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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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Modulation of BAZ2 Proteins as a Potential Therapeutic Strategy in Cancer and Neurological Disorders
… by exploiting PROteolysis Targeting Chimera (PROTAC) technology. This innovative approach allows protein degradation by fostering interactions between an E3 ubiquitin ligase and a POI, effectively directing the ubiquitin-proteasome system to eliminate the target protein. In this study, we …
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A study of novel tools to measure and perturb Aurora Kinase A protein stability
… compounds called proteolysis targeting chimeras (PROTACs) and consisted of MLN8237, a small molecule inhibitor of AurKA, linked to pomalidomide, a chemical ligand for the Cereblon (CRB) E3 ligase. The PROTAC works by ectopically recruiting AurKA to CRB, resulting in its ubiquitination and …
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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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The Design, Synthesis and in vitro Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Degradation of Protein Arginine Methyltransferase 1
… to the clinic. The degradation of PRMT1 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 …
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SGK3 activity and regulation in PI3K-Akt pathway inhibitor resistance in breast cancer
… the Ciulli lab, designed and characterised SGK3-PROTAC1, a Proteolysis Targeting Chimera (PROTAC) which targeted SGK3 for specific ubiquitylation by VHL E3 ligase and subsequent proteasomal degradation. I demonstrated by quantitative Mass Spectrometry that SGK3-PROTAC1 mediated degradation was …
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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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STRATEGIES TO TARGET HUMAN D-ASPARTATE OXIDASE AND MODULATE ENDOGENOUS D-ASPARTATE LEVELS IN SCHIZOPHRENIA
… degradation via the proteasomes. To this aim, PROTAC molecules were synthetised linking olanzapine to either lenalidomide or (VH032)-Me designed to recruit Cereblon or Von Hippel–Lindau (VHL) E3 ligases, respectively. These compounds were tested both in vitro and in cell lines for the …
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Metastatic Reactivation and Progression Result From Fak-Mediated Disruption of Innate Immune Signaling
… degradation with proteolysis targeting chimera (PROTAC) of Fak, but not inhibition of its kinase activity, restores interferon production and enhances the sensitivity of incipient and established metastases to Sting agonists and immune checkpoint blockade. These findings highlight a novel, …
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The impact of ARID1A loss on ER+ breast cancer: mechanistic insights and therapeutic opportunities
… II C-terminal domain. Using a cutting-edge PROTAC approach targeting BRD2, BRD3, and BRD4, in vivo studies showed impaired growth of ARID1A-depleted tumours and a reduction in metastatic burden. Further investigations in other tumour types supported these findings, suggesting a pan-cancer …
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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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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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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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Functional investigation of PERIOD in the mammalian circadian clock
… and proteolysis targeting chimera (PROTAC) acute knockdowns. Next, PER2 activity changes over the cellular circadian cycle were assessed through time-resolved mass spectrometry of the PER2 interactome. Finally, CRISPR-mediated gene editing was used to investigate the circadian …
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Targeting Transcription Factors in Neuroblastoma: Development of Aurora Kinase A/N-Myc Degraders and ID2 Chemical Probes
… developed using proteolysis targeting chimera (PROTAC) technology. The representative compound, 2.3 (HLB-0532259), potently decreases N-Myc protein levels following the induced degradation of Aurora-A. Tandem mass tag (TMT)-based proteomic analysis has demonstrated that 2.3 possesses excellent …
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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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