Vaughn, Zoe
(2023)
Design, Synthesis, and Biological Evaluation of Small Molecules HDAC8 Inhibitors for use in Acute Kidney Injury (AKI).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Acute Kidney Injury (AKI) is the most common cause of organ dysfunction in critically ill patients. AKI is also a major risk factor for developing chronic kidney disease (CKD), which can ultimately lead to end stage kidney disease, the need of dialysis, or even kidney transplant. The work described contributes to addressing the unmet clinical need through validation of a target for AKI using phenotypic screens in zebrafish, and optimization of the validated target. To investigate histone deacetylase 8 (HDAC8) as a target for AKI we evaluated multiple inhibitors with a variety of scaffold that ranged in potencies and selectivity’s in a series of increasingly stringent AKI assays. PCI-34051, a potent and selective HDAC8 inhibitor was shown to be effective in increasingly stringent models of AKI. Classical HDAC inhibitors (HDACi) such as PCI-34051 rely on a three-part pharmacophore, the cap, linker, and zinc binding group (ZBG) with hydroxamic acids often being utilized as the ZBG because of high metal binding affinity. However, hydroxamic acid ZBG can lead to limitations of efficacy and toxicity, thus emphasizing the need for the development of novel HDACis. In the HDAC active site there is a deep pocket within the enzyme responsible for generating the next catalytic cycle that is known as the “foot pocket” or acetate release channel. Herein I describe inhibitors that were developed to mitigate the negative effects of hydroxamic acids and improve potency and selectivity by extending the HDACi pharmacophore deeper into the pocket as well as relying on novel zinc chelation moiety.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
19 July 2023 |
| Date Type: |
Publication |
| Defense Date: |
9 June 2023 |
| Approval Date: |
19 July 2023 |
| Submission Date: |
17 July 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
240 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Acute Kidney Injury, Histone Deacetylase, Inhibitors, PCI-34051, Pharmacophore, Hydroxamic Acids, Catalytic Zinc, Hybridization, Zebrafish, Phenotypic Screens, Acetate Release Channel |
| Date Deposited: |
19 Jul 2023 19:31 |
| Last Modified: |
19 Jul 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45104 |
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