Date of Award

5-14-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John Chisholm

Abstract

The PI3K pathway is a biological pathway of great importance to the biomedical community. PI3K and mutations associated with it have often associated as the cause for various disease states due to its role in signaling other enzymes such as AKT. Targeting PI3K is one way to help regulate the PI3K pathway but there are other enzymes such as SHIP that also contribute to the delicate balance of the cell. It has been proposed that the modulation of SHIP could also provide some therapeutic benefit as its behavior opposes that of PI3K. Detailed in this work is the design and synthesis of aminosteroid inhibitors as well as agonist studies involving the optimization of an AQX-1125 analog synthetic route. These inhibitors and agonists may be used further to help analyze the role SHIP plays in certain disease states such as Alzheimer’s Disease. Proteolysis Targeting Chimeras or PROTACs have become a topic of discussion in the biomedical community in recent years. They provide an alternate route of modulating proteins by lowering protein levels in cells as opposed to inhibitor-based strategies. The potential for this strategy to be of therapeutic relevance is immense as it allows for the targeting of proteins and receptors, even ones that do not have enzymatic roles. A proper PROTAC can also incorporate a weak binding inhibitor and still be a potent and selective therapeutic which expands the library of possibilities for protein targets. With these studies, two proposed SHIP based PROTACs were synthesized and made. If proven to degrade SHIP, these molecules could provide valuable knowledge towards the role SHIP plays in disease. These molecules would also be useful in probing the scaffolding role of SHIP which has not been investigated in human disease.

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Open Access

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