Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 42 for “"Bromodomain"”.
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Synthesis and biological evaluation of novel small molecule bromodomain inhibitors
… without changing the primary DNA sequence. Bromodomain-containing proteins are responsible for recognising acetylated residues on histone tails, recruiting transcriptional machinery and thus facilitating gene transcription. Small molecule bromodomain inhibitors prevent this recognition, thus …
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Development of peptide-based 19F MRI agents and BPTF-bromodomain inhibitors
… first reported small molecule inhibitor of the bromodomain of a protein called BPTF, was discovered in the Pomerantz lab in 2015. As BPTF is a relatively understudied protein, there exists a need to improve the potency of AU1 as a probe for the various functions of its bromodomain, as it has …
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Control tools for flow chemistry processing and their application to the synthesis of bromodomain inhibitors
Flow chemistry and continuous processing techniques are now frequently used in synthetic laboratories, taking advantage of the ability to contain reactive or hazardous intermediates and to perform moderate scale-up processes for important compounds. However, only a limited number of methods and …
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Structural studies of paired PHD finger-bromodomain chromatin-binding modules: targeting epigenetic readers with chemical probes
The use of chemical probes is a powerful tool that can help to address important biological questions.<br/><br/>The study presented in this thesis aims to target reader domains of chromatin-associated proteins with small molecules, in order to provide information on their ligandability, useful to …
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Mechanistic and Therapeutic Insights for Epigenetic Regulation in Cancer Development
… with increased levels of chromatin regulator/BET bromodomain protein BRD4, and paradoxically, sensitivity and resistance to BET bromodomain inhibition with small molecule inhibitor JQ1. Indeed, genetic and pharmacological inhibition of BRD4 profoundly suppresses both growth and tumorigenesis of …
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THE PHD FINGER OF SP140: A STRUCTURAL AND FUNCTIONAL STUDY
… 588-661), a PHD finger (residues 692-734) and a bromodomain (residues 756-859). In this thesis we investigated Sp140 PHD finger both at functional and structural level. Structural determination was performed in solution by means of NMR spectroscopy. Analysis of 1H-15N HSQC spectra of Sp140 15N …
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Genetic and mechanistic analysis of heterochromatin spreading in the yeast S.cerevisiae
… mutational analysis identified YTA7, a novel bromodomain containing gene, as being required for full barrier activity of the HMR tRNA gene. This provided some of the first evidence demonstrating a role for bromodomain proteins in boundary function. RPD3, a histone deacetylase gene was also …
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STAT3-protein interactions in IL-6/gp130 signaling
… the STAT3 NH2-terminal domain maps to the p300 bromodomain and the STAT3 NH2-terminal acetylation induced by p300 stabilizes this interaction. Finally, the deletion of p300 bromodomain not only reduces its binding affinity to STAT3 but also inhibits its association to the socs3 promoter. Our …
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Predictive Modelling of the Primary and Secondary Pharmacology of Compounds in Drug Discovery
… models, on the same bioactivity dataset for the bromodomain-containing proteins. Furthermore, we established the applicability domain of the model by employing conformal prediction, which was further used to aid the selection of compounds for prospective experimental testing in bromodomain …
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Computational dissection and prediction of cancer immunotherapy response
… targeting this signature with acetylation-reader bromodomain inhibitors would allow suppression of multiple resistance mechanisms at once. We show that bromodomain inhibitors exhibit considerable synergism with anti-PD1 in reducing tumor volume in murine melanoma transplantation models, and this …
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A ‘bump-&-hole’ approach for engineering allele-selective inhibition of the BET bromodomains
… chemical genetic work is the BET family of bromodomains – 8 closely related, and structurally conserved, epigenetic acetyl-lysine reader domains that so far has defied single-bromodomain inhibition. The Alessio Ciulli lab has previously designed a proof-of-concept ‘bump-&-hole’ system to …
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Targeting Myc-driven tumours - BETing on ATR
… a novel and orally bio-available BET bromodomain inhibitor (BETi) RVX2135. We also identified BET bromodomain proteins as a valuable therapeutic target against MYC driven tumours in vitro and in vivo. Gene expression profiling to identify these transcriptional changes enabled us to …
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Development of Protein Degraders Inspired by Chemical Modifications
… transferability assessment. First, a Dha-based bromodomain-containing protein 4 (BRD4) degrader was synthesized and demonstrated to induce consistent attenuation of BRD4 levels at micromolar potency. Subsequent optimization revealed that a spacer is not required for Dha-based degrader design, …
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HISTONE LYSINE METHYLTRANSFERASE NSD3 GOVERNS TRANSCRIPTIONAL PROGRAMS THAT DRIVE PANCREATIC NEUROENDOCRINE TUMORS (PANNETS)
… NSD3 that target growth-signaling pathways and bromodomain inhibition rendering tumor growth in vitro.</p> <p>Together, this work elucidates the role of NSD3 in tumorigenesis and provides a rationale for this KMT as an actionable for neuroendocrine tumors.</p>
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Identifying Molecular Targets and Validating Novel Therapies For Ovarian Cancer
… validate our tool, we determined that Bromodomain and Extra-Terminal motif inhibitors (BETis), which target proteins such as BRD4, held the greatest promise to produce therapeutic effects and impact relevant oncogenic gene targets, such as Notch3,<strong> </strong>in this disease. In …
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Trim24 Orchestrates Metabolic Reprogramming and Emt In Breast Cancer
… as a co-regulator of nuclear receptors and a PHD/Bromodomain reader of specific histone modifications. TRIM24 expression correlates with poor prognosis of breast cancer, but the mechanisms of TRIM24-mediated oncogenesis are unknown. In the first part of my thesis, I found that TRIM24 is aberrantly …
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Investigation of novel therapeutic strategies in B cell and antibody mediated disease
… study investigating the potential efficacy of bromodomain inhibitors in reducing antibody-mediated immune cell activation. Immune complexed antigen can activate mononuclear phagocytes (MNP), comprising macrophages and dendritic cells (DCs), via ligation of Fc gamma receptors (FcγR), that bind …
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Investigating the Mechanisms of Resistance to Dual PI3K/MTOR Inhibitor in PIK3CA Mutant Basal Like Bladder Cancer
… targeted inhibition. Interestingly, we observed bromodomain inhibition by JQ1 to be the most effective strategy to re-sensitize resistant cells to PI3K targeted therapy. Overall, this project provides a predictive paradigm of response to PI3K targeted inhibition in PIK3CA mutant MIBC and sets the …
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Epigenetic Modification as a Therapeutic Target in BRAFV600E-mutated Metastatic Colorectal Cancer
… CRC. Additionally, the combination of bromodomain and extra-terminal protein (BET) inhibition in vivo with standard MAPK-targeted therapies showed deeper inhibition of the MAPK signaling and improved efficacy. Enhancer blockade disrupted the regulation of core transcription factors …
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Molecular regulation of BRD3 in forward programming of Megakaryocytes
… BRD2, BRD4 and BRDT, is classified within the bromodomain and extra terminal (BET) family, specialised in recognising and binding to acetylated lysine residues. In this project, I studied the functions of BRD3 during megakaryopoiesis, the process that leads to platelet formation. Because …
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