Date of Award

Summer 8-12-2024

Embargo Period

8-1-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

Additional College

College of Pharmacy

First Advisor

Patrick M. Woster

Second Advisor

Yuri K. Peterson

Third Advisor

Pieter B. Burger

Fourth Advisor

Nathan G. Dolloff

Fifth Advisor

Danyelle Townsend

Sixth Advisor

Abhiram Maddi

Abstract

This study describes the synthesis and biological evaluation of small molecule KDM4B inhibitors for use in modulating immune responses in periodontal disease (PD). Periodontal disease begins with the accumulation of bacterial plaque in the oral cavity, triggering an inflammatory response that damages host tissues. Despite standard treatments such as scaling and root planing (SRP) to remove biofilm, the host immune response can remain hyperactive, leading to ongoing tissue destruction and bacterial-driven inflammatory bone loss.

Research suggests that the microenvironment of periodontal disease induces epigenetic alterations, particularly through increased activity of lysine-specific demethylase 4B (KDM4B). Previous studies using a murine macrophage model demonstrated that periodontal inflammation could be induced by exposing macrophages to lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans (A.a.), a pathogen associated with aggressive periodontitis. This form of periodontitis is notably resistant to SRP and persists even in the absence of plaque, presenting significant clinical challenges. Further, a non-selective KDM inhibitor reversed the pro-inflammatory response of macrophages to A.a. LPS in vitro, highlighting KDMs as a promising therapeutic target.

In the current study, we focused on improving the selective of KDM inhibitors leading to a first-in-class KDM4B inhibitor. The synthesis and evaluation of derivatives led to the discovery of a compound 39, which exhibited an IC50 of 170 nM against recombinant KDM4B and demonstrated immunosuppressive activity in the Aa LPS challenge model. Additionally, 39 reduced osteoclast formation in vitro. These findings suggest that compound 39 should continue to be developed as a potential therapeutic agent for modulating the immune response in periodontal disease.

Rights

Copyright is held by the author. All rights reserved.

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