Synthesis, characterization, and evaluation of KDM4B inhibitors to attenuate inflammatory host immune response in periodontitis

Abstract Periodontal disease begins with bacterial plaque buildup in the oral cavity, inciting an inflammatory response that results in subsequent tissue damage. Even after standard treatment like scaling and root planning (SRP) to remove plaque and biofilm, the host immune response can remain hyper-active, perpetuating further tissue destruction. In these cases, aggressive periodontitis is resistant to SRP and the inflammatory response may persist, even in the absence of plaque, presenting a significant clinical challenge. Previous experiments have provided a validated model of periodontal inflammation by exposing murine macrophages to lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans ( Aa ), a pathogen linked to aggressive periodontitis. Using this model, we have previously demonstrated that the periodontal disease microenvironment triggers epigenetic changes, notably heightened lysine-specific demethylase 4B (KDM4B) activity. Data indicate that the KDM4B inhibitor ML324 can reverse the macrophage-mediated pro-inflammatory response induced by Aa LPS in vitro, providing compelling evidence for KDM4B as a rational therapeutic target for periodontal disease. In the present studies, a cohort of compounds was developed as potential KDM4B inhibitors. Synthesis and characterization of derivatives led to the discovery of compound 14 with an IC 50 of 170 nM against KDM4B and immunosuppressive activity in the Aa LPS challenge model. These results suggest KDM4B inhibitors as potential therapeutic agents for modulating the immune response for periodontal disease.