Epigenetic Compounds Stimulating Dental Bone Repair

PROJECT SUMMARY/ABSTRACT Periodontitis is caused by microbial invasion around the teeth that triggers chronic inflammation, resulting in the degeneration of periodontal tissues in the oral cavity. Chronic periodontal inflammation perturbs the balance of bone-forming osteoblasts and bone-resorbing osteoblasts in alveolar bone, resulting in net bone loss. This loss of alveolar bone compromises tooth stability and makes implantation of restorative dental devices either problematic or impossible. The increasing prevalence of periodontitis-related bone resorption, especially in the aging population, requires novel bone restorative approaches. Currently, there are limited options for stimulating the growth of alveolar bone in dental practice and some can be prohibitively expensive for patients. A small molecule-based therapy, such as we are proposing here, would lower costs and could be designed to minimize side effects as well as to have wide versatility for incorporation into a variety of delivery matrices. One of the epigenetic enzymes, EHZ2, promotes trimethylation of the H3 histone 27 lysine, ultimately silencing osteoblast related genes by inducing heterochromatin formation. Our published studies consistently show that pharmacological inhibition of EZH2’s actions increases the expression of osteoblast-related genes and stimulates osteogenesis both in cell culture and in mice. In this application we address the compelling clinical need for alveolar bone regeneration by developing novel osteogenic small-molecule pharmacotherapies for local delivery that act via inhibition of the epigenetic EZH2 bone anabolic pathway. Cayman Chemical Company, Inc. will create novel EZH2 inhibitor compounds with pharmacological characteristics that make them more suitable for the stimulation of bone formation in dental applications than the EZH2 inhibitors currently being developed for treating cancer. In our medicinal chemistry approach, we will use an Artificial Intelligence-driven system to design novel inhibitors, which will then be synthesized and tested to determine their potency for EZH2 inhibition, stimulation of bone formation in mouse and human cell culture assays, their physiochemical properties, and their metabolic stability. Iterative feedback of data from the screening will train the design model to yield compounds with the desired features of high potency for bone formation, good aqueous solubility, and high metabolic turnover. The best compounds will be tested for their pharmacokinetic profiles in mice as well as in an initial safety screen using biochemical assays. In Phase II, the compound with the best characteristics for local application in dental use will be further optimized and then tested in animal models of alveolar bone restoration under innate and inflammatory conditions associated with periodontitis.