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.
Results
Showing 1 to 20 of 21 for “"target engagement"”.
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Chemical Tools for Exploring Metabolite Interactions with Nuclear Receptors and Beyond
… by these methods. New activity-based probes and targeted chemical reporters of specific protein families are thus needed to characterize their endogenous and exogenous ligands for fundamental biology and drug discovery. In this thesis, we describe two projects aimed at developing chemical probes …
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QUANTITATIVE PROTEOMIC APPROACHES TO STUDY DRUG MECHANISM OF ACTION
… bind specific nucleophilic sites in the protein target. Covalent inhibition of oncogenic protein kinases allows to obtain a stronger and prolonged therapeutic effect compared to reversible inhibition; however, the choice of the dose to be administered to patients and the evaluation of the …
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Chemical probes for studying cyclooxygenase-2 and nitric oxide in living systems
… undergo a selective, observable change following target engagement. Activity-based sensing is a powerful expansion of molecular imaging because it measures chemical reactivity rather than concentration. Chapter 1 serves as an introduction to molecular imaging with a historical tone. It also …
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Translational phosphoproteomics methods to identify biomarkers and novel therapeutic targets
… tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. In the last part of thesis, we demonstrate the application of quantitative tyrosine phosphorylation in identifying novel therapeutic targets in …
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The influence of positively charged nitrogen species on compound accumulation and activity in gram-negative bacteria
… of a primary amine resulted in the disruption of target engagement. Therefore, it would be advantageous to have alternate functional groups that facilitate accumulation in Gram-negative bacteria but offer different interactions with a given target protein. Here we report that other positively …
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Hijacking Cancer Signaling: First-in-class JPRK-targeting Ligands for Fibrolamellar Hepatocellular Carcinoma
… silico fragment screening against an un-drugged target and concluding with a collaboration to evaluate single digit nanomolar potent and >500-fold selective drug candidates in patient derived xenografts. Fibrolamellar hepatocellular carcinoma is a rare un-treated liver cancer driven by a fusion …
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piRNA-dependent transcriptional gene silencing during Drosophila oogenesis and embryogenesis
… antisense piRNAs as guides. Following target engagement, the gonad-specific protein Panoramix (Panx) is recruited and induces transcriptional gene silencing (TGS) by connecting to the general chromatin silencing machinery of the cell resulting in changes of the epigenetic chromatin …
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Ring distortion of the alkaloid sinomenine and novel prodrug approaches to broad-spectrum antibiotics
… installation of the nitrogen without disturbing target engagement. A solution to this involves appendage of ionizable nitrogens on a prodrug moiety such that it crosses the outer membrane and is cleaved within Gram-negative bacteria, releasing the active antibiotic. Such novel strategy can be a …
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Selective Degradation of Aggregated Tau Protein Via Vectored Nanobody-TRIM21 RING Fusion Constructs
… common neurodegenerative diseases and is a key target in therapeutic development. Whilst promising in pre-clinical models, tau targeting antibodies have performed poorly in clinical trials, potentially due to low target engagement. Such antibodies rarely access the intracellular domain where the …
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The Design, Synthesis and in vitro Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Degradation of Protein Arginine Methyltransferase 1
… cancer cells to other treatments. Therefore, targeting PRMT1 is a promising therapeutic strategy in cancer treatment. Published inhibitors for PRMT1 show poor selectivity and dose-limiting toxicities that have precluded their translation to the clinic. The degradation of PRMT1 using a PROTAC …
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Identification and Optimization of Small Molecule Binders for ALK2, USP5, and DCAF1
… the optimization of small molecule binders targeting three proteins involved in the development of various cancers: Activin receptor-like kinase 2 (ALK2), ubiquitin-specific protease 5 (USP5), and DDB1-cullin4 associated factor 1 (DCAF1). For ALK2, a kinase involved in the development of …
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Design, synthesis and biological evaluation of sphingosine kinase inhibitors for the treatment of prostate cancer
… studies have demonstrated that SK is a promising target for the treatment of cancer and the development of novel isoform-selective SK inhibitors to treat human cancers is of major interest. To date, inhibitors for this enzyme have either been selective for SK1 or non-selective for both isoforms. …
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NF1 AS A REGULATOR OF CYTOSKELETON DYNAMICS AND BIOMARKER FOR DECISION-MAKING IN HER2-POSITIVE BREAST CANCER
… was specific to the mertansine MT-targeting component (DM1) since it was i) replicated by the naked payload but not the antibody alone; ii) absent with other ADCs (i.e.: trastuzumab deruxtecan [T-DXd]); iii) not accompanied by increased T-DM1 uptake; and iv) associated with …
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Antibiotic Drug Discovery Targeting Bacterial Metabolism
… to various mutations in the sulfonamide target dihydropteroate synthase. This information currently guides the development of next-generation antifolates designed to avoid these characterized resistance strategies. In the subsequent chapter, a conditional metabolic screening approach was …
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Development of imaging techniques to assess tumour cell death
Cell death is an important imaging target for assessing early tumour treatment response and the effectiveness of therapy. Traditionally, anatomical imaging modalities measure changes in tumour size (Response Evaluation Criteria in Solid Tumours (RECIST)). More recently these assessments have also …
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Targeting Transcription Factors in Neuroblastoma: Development of Aurora Kinase A/N-Myc Degraders and ID2 Chemical Probes
Transcription factors (TFs) are promising targets in oncology due to their critical rolesin dysregulated signaling pathways in tumor cells. However, targeting TFs with small molecules is challenging as they frequently lack endogenous ligands or amenable ligandbinding sites. The thesis will discuss …
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Different approaches to biomarker research for ALS: in search of novel neuronal markers associated with extracellular vesicles
… to aid in diagnosis and prognosis, study target engagement, and facilitate participation in clinical research. Of all the proposed biomarkers, neurofilament light chain (NfL) is the most promising, having been demonstrated to be useful as both a diagnostic and a prognostic and …
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Discovery and Optimization of a Family of Naturally Encoded Antibiotic Compounds that Evade Antibiotic
… antibiotics that may possess the same molecular targets and resistance evasion ability seen with cilagicin. This structure-based screen yields three BGCs predicted to produce natural analogs of cilagicin. synBNPs for the products of each of these three clusters are synthesized and the resulting …
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Design, synthesis, and structural elucidation of spiroligomers for targeted molecular recognition
… molecular space, side-chain orientation, and target engagement across host-guest systems and next-generation functional systems. Scalable synthetic routes were developed to access stereochemically pure, functionalized bis-amino acid building blocks. Compatible with automated solid-phase …
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Developing a selective sphingosine-1-phosphate-5 (s1p5) radiotracer to image oligodendrocytes using preclinical positron emission tomography (PET)
… the central nervous system in vivo. The ligands target the sphingosine-1-phosphate-5 (S1P5) receptor as a potential marker of oligodendrocyte function with PET. The ligands selected (TEFM180 and TEFM78) were developed from a drug development library of agonists targeting S1P5 that had shown high …
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