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Design, Synthesis, and Biological Evaluation of Small Molecules HDAC8 Inhibitors for use in Acute Kidney Injury (AKI)

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 (Unpublished)

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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Status: Unpublished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:
CreatorsEmailPitt UsernameORCID
Vaughn, Zoeznv1@pitt.eduznv10000-0002-7006-673X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSmith, Randellsmithrb@pitt.edusmithrb
Committee CoChairHukriede, Neilhukriede@pitt.eduhukriede
Committee MemberJohnston, Paulpaj18@pitt.edupaj18
Committee MemberFloreancig, Paulflorean@pitt.eduflorean
Committee MemberRohan, Lisarohanl@pitt.edurohanl
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 2023 19:31
URI: http://d-scholarship.pitt.edu/id/eprint/45104

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