Description:
Technology: Researchers at MUSC have discovered a series of novel small molecules that contain potent immunosuppressive activity and can be used as the new treatment for periodontal disease (PD). PD is caused by bacteria infection in dental plaque, which leads to the inflammation response in the area of gums, periodontal ligament or alveolar bone. While most therapy for PD targets bacteria, the host immune response is responsible for driving tissue damage and bone loss in severe PD. MUSC researchers established that the histone demethylase KDM4B is a potential drug target for the treatment of PD (Figure 1).
Experimental results both in vitro and in vivo have shown that the abundance of KDM4B is correlated with inflammation, and inhibition significantly reduces the As-LPS-induced immune response in primary macrophages, with a significant reduction of IL-6 and TNF-α expression and secretion (data not shown). Moreover, KDM4B inhibition with a previously identified inhibitor ML324 prevents osteoclast formation induced by As-LPS or RANK-L in murine bone marrow (Figure 2). The data indicates that the immunosuppression promoted by KDM4B inhibition reduces osteoclastogenesis, a main factor of PD.
Using virtual and physical screening techniques, the researchers identified novel compounds 40 and 42 that are immunosuppressive via inhibiting KDM4B. The two compounds occupy the same space of KDM4B active site as the natural ligand H3K9me3 and the cofactor 2-oxoglutarate, and showed significant IL-6 reduction after LPS challenge (Figure 3). In summary, these novel small molecule inhibitors are potent KDM4B inhibitors and can be used as an attractive therapeutic treatment for PD, and other hyper-inflammatory diseases.
Overview: Periodontal disease (PD) is initiated by bacterial plaque buildup in the oral cavity which initiates a hyper-inflammatory cascade, resulting in the destruction of host tissues. PD affects 46% of Americans with no effective adjunctive therapies available. While most pharmacotherapy for PD targets bacteria, the host immune response is responsible for driving tissue damage and bone loss in severe disease. MUSC researchers identified that the histone demethylase KDM4B is correlated with inflammation response, suggesting that the enzyme is a potential drug target for PD. The discovery of the novel KDM4B inhibitor can be a revolutionary therapeutic drug for PD treatment.
Applications: Periodontal disease (PD), Immunosuppression
Advantages: Treatment of periodontal disease via targeting the host immune response. The small molecules prevent the release of inflammatory signals and osteoclastogenesis that cause periodontitis to progress.
Key Words: Periodontal disease (PD), KDM4B, Immunosuppression, Osteoclastogenesis
Publication: Kirkpatrick et al.,"Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis."Epigenetics,2018, 13(5):557-572
Inventors: Patrick M. Woster, Joy Kirkpatrick
Patent Status: Provisional filed in June 2019
MUSC-FRD Technology ID: P1872