Graduation Year
2023
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Chemistry
Major Professor
James W. Leahy, Ph.D.
Committee Member
Edward Turos, Ph.D.
Committee Member
Andrii Monastyrskyi, Ph.D.
Committee Member
Yu Chen, Ph.D.
Keywords
STING, immunity, Alzheimer’s, Slingshot homology, SSH1, Clonixin
Abstract
This work details the effort toward structure-activity-relationship (SAR) studies and synthesis of the small molecule modulators of two non-traditional drug targets. The first part of this manuscript (chapters 1–2) will discuss the collaborative work and synthesis of an inhibitor of Slingshot Homology 1 (SSH1) with the potential therapeutic application toward Alzheimer’s Disease (AD) treatment. The second part (chapters 3–6) will discuss the synthetic efforts toward modulation of a protein target known as STING, or stimulator of interferon genes, with the therapeutic application toward autoimmune disease or anti-tumor activity.
AD is a progressive and degenerative illness that holds the title of being one of the lead causes of death worldwide. It has long been theorized that this disease is caused by the formation of toxic plaques and tangles in the brain. SSH1 is a phosphatase that, through knockout studies, has shown to play a role in the manifestation of such plaques and tangles. Thus, it is hypothesized that the inhibition of this pathway can lead to a new treatment for AD. For a long time, AD treatment has not addressed the underlying biology of disease. Additionally, while there is much known about kinase inhibitors (the biological opposition to phosphatases), there is around a ten-fold decrease in information on phosphatases. Prior screening campaigns and work on this project focused on the SAR studies of one of two leading hit molecules. This work will outline the efforts toward analogs synthesis of the second of those two molecules, focused on the bioisosteric replacement of the various functional groups present on our initial hit compound. Disclosed in this manuscript are the successful synthetic pathway toward sixteen analogs, fourteen of which were tested via an in vitro colorimetric assay to analyze their potency as SSH1 inhibitors. Of the fourteen tested, two analogs have shown to have significant activity. Further SAR studies have begun with the goal of exploiting these favorable changes to our initial hit compound with the overall goal of future analog development.
The innate immune system is the first line of defense toward potential pathogens in mammals. A key protein in this process is the recognition of cytosolic DNA by STING leading to downstream production of type 1 interferon. The STING protein is a versatile target for drug discovery with a large variety of applications. Prior work in this area has shown that agonists of STING have led toward anti-cancer and anti-tumor activity, while antagonists of this protein have promising applications toward modulating autoimmune disease. Recent efforts through academic collaboration have shown that clonixeril, a known anti-inflammatory drug, acts in a concentration-dependent manner as either a partial agonist or potent antagonist of this pathway in substoichiometric concentrations. The latter half of this manuscript outlines our SAR efforts toward optimizing STING modulation with the synthesis of 40 analogs of clonixeril, many of which exhibit high-affinity binding concentrations in the attomolar range. Further work into the biological activity of these compounds is currently ongoing.
Scholar Commons Citation
Nunziata, Jamie, "Synthesis of Small Molecule Modulators of Non-Traditional Drug Targets" (2023). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/9912
