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NEW APPROACHES FOR QUANTIFICATION OF ENGAGEMENT AND MODULATION OF TARGETS BY SMALL MOLECULES IN LIVING CELLS
Andres, Angelo Eusebio
Andres, Angelo Eusebio
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Abstract
The development of novel therapeutics for cancer therapy is challenged by limitations in translating in vitro observations into in vivo efficacy. These limitations can result from mechanisms of resistance to chemotherapeutics and by disconnected methods in drug discovery that are driven by assays of protein-drug interactions that are not sufficiently relevant to physiological conditions found in living systems. As an approach to overcome these limitations and advance the field of microtubule-targeted cancer therapy, we utilized fluorescent derivatives or chimeras of the anticancer drug Taxol to develop cell-based assays for the discovery of molecules that engage the Taxol binding site of microtubules or that modulate its polymerization. Compared to conventional biochemical assays, these methods provide higher throughput for quantifying apparent binding affinities of agents to microtubules in living intact cells.In a second scientific approach, we investigated chimeric molecules that possess multifunctional properties to enable novel therapeutic modalities. One such modality is lysosome targeting chimeras (LYTACs), which aim to target extracellular and membrane proteins for targeted degradation through the cellular lysosomal pathway. LYTAC systems developed to date require the engagement of exogenous bifunctional small molecules or antibodies by endogenous receptors such as the cation-independent mannose-6-phosphate receptor, or the asiaglycoprotein receptor, to deliver extracellular proteins into lysosomes. In this dissertation, we provide proof of concept that small molecules developed by our group can function as both a bifunctional ligand and a synthetic cellular receptor to capture and recruit exogenous model proteins for delivery into cellular lysosomes for degradation.
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Date
2022-05-31
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University of Kansas
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This item contains archived web content.
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Available after May 31, 2028
Adobe PDF, 24.34 MB
- Embargoed until 2028-05-31
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Keywords
Chemistry, Biology, Molecular biology, Chemical Biology, Drug Discovery, LYTAC, Microtubule, Targeted Protein Degradation, Taxol