Periodontal disease (PD) is characterized by accumulation of bacterial plaque in the oral cavity that causes an inflammatory response and can lead to severe tissue damage. The current standard of care for patients with PD entails scaling and root planing, which focuses on elimination of the biofilm buildup. This method is temporary, and fails to address the underlying inflammatory process, resulting in continual damage and the need for recurring treatments. Previous research in our laboratory established that upregulation of KDM4B, a 2-oxoglutarate-dependent histone lysine demethylase that controls epigenetic regulation of gene expression, directly affects the heightened immune response in PD. Overexpression of KDM4B leads to an increase in pro-inflammatory cytokine (PIC) production, resulting in inflammation and corresponding tissue damage. In our murine bone marrow-derived macrophage model of PD, PIC expression is initiated by stimulation with lipopolysaccharide from <i>Aggregatibacter actinomycetemcomitans, </i>an oral pathogen that is often associated with localized aggressive periodontitis. We reasoned that a small molecule inhibitor of KDM4B could effectively decrease PIC production, allowing for a more effective treatment of periodontal disease that targets the underlying inflammatory process. Previously published inhibitors of KDM4 lack potency and exhibit poor selectivity between KDM4 homologs, We have now identified a series of drug-like small molecule inhibitors of KDM4B that promote the down regulation of PIC gene expression in the macrophage model described above. In this presentation, we will describe the optimization of our current hit compounds and their biological characterization. These optimized compounds will elicit more efficacious immunosuppressive activity, and will be useful as chemical probes to elucidate the mechanism by which KDM4B inhibition leads to an attenuated inflammatory response. Mitigation of inflammatory response in a localized manner could also provide a new and effective treatment for aggressive PD.

Synthesis and identification of KDM4B inhibitors for the alleviation of inflammation in periodontal disease

ACS Spring 2022

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