Drug Repurposing in Dentistry: Towards Application of Small Molecules in Dentin Repair

Abstract

One of the main goals of dentistry is the natural preservation of the tooth structure following damage. This is particularly implicated in deep dental cavities affecting dentin and pulp, where odontoblast survival is jeopardized. This activates pulp stem cells and differentiation of new odontoblast-like cells, accompanied by increased Wnt signaling. Our group has shown that delivery of small molecule inhibitors of GSK3 stimulates Wnt/β-catenin signaling in the tooth cavity with pulp exposure and results in effective promotion of dentin repair. Small molecules are a good therapeutic option due to their ability to pass across cell membranes and reach target. Here, we investigate a range of non-GSK3 target small molecules that are currently used for treatment of various medical conditions based on other kinase inhibitory properties. We analyzed the ability of these drugs to stimulate Wnt signaling activity by off-target inhibition of GSK3. Our results show that a c-Met inhibitor, has the ability to stimulate Wnt/β-catenin pathway in dental pulp cells in vitro at low concentrations. This work is an example of drug repurposing for dentistry and suggests a candidate drug to be tested in vivo for natural dentin repair. This approach bypasses the high level of economical and time investment that are usually required in novel drug discoveries.

Facilitation of Reparative Dentin Using a Drug Repositioning Approach With 4-Phenylbutric Acid

“…Drug repositioning is intended to apply alternative uses for a drug that is developed by another investigator and besides its original medical purpose. It has advantages in nancial and time savings for drug development with the lower failure risk and reduced drug investigating time and costs [39][40][41] .…”

Small molecule-mediated regenerative engineering for craniofacial and dentoalveolar bone

“…Techniques for small molecule screening such as cell panel screening are widely used for investigating in vitro biological mechanism and drug discovery ( Figure 1 ). A number of groups have investigated the role of various glycogen synthase kinase-3 (GSK3)-inhibiting small molecules in the regeneration and differentiation of odontogenic stem cells, primarily endogenous to tissues of the dental pulp and dentin ( Neves et al, 2017 ; Neves & Sharpe, 2018 ; Birjandi et al, 2020 ; Masuda et al, 2020 ). GSK3 has been identified as a key enzyme in the modulation of many signaling pathways responsible for the growth and maturation of bone, including those common to the formation of craniofacial and dentoalveolar tissues e.g., the Wnt/β-catenin pathway which has been demarcated as a pertinent cascade in stem cell differentiation and the regulation of dentin repair.…”

“…GSK3 has been identified as a key enzyme in the modulation of many signaling pathways responsible for the growth and maturation of bone, including those common to the formation of craniofacial and dentoalveolar tissues e.g., the Wnt/β-catenin pathway which has been demarcated as a pertinent cascade in stem cell differentiation and the regulation of dentin repair. One such study has shown that five unique small molecule drugs known to work through different mechanisms of action (Famotidine, Olanzapine, Naproxen, Cromolyn, and Tivantinib) are capable of acting as inhibitory agents against GSK3 ( Birjandi et al, 2020 ). Of these drugs, Tivantinib—a non-ATP competitive small molecule mainly used in the treatment of hepatocellular carcinoma—was observed to incite Axin2 expression and Wnt/β-catenin pathway signaling at a low concentration (50 nM) while simultaneously maintaining dental pulp cell viability through inconsequential levels of toxicity, thus potentially making it a suitable candidate for in vivo studies on the natural regeneration of odontoblasts necessary for reversing profound dentinal lesions and enhancing dentin preservation.…”

“…Additionally, they have been utilized by some researchers as resourceful probes into the intricacies of less understood biological pathways. The regenerative properties demonstrated by some small molecules have shown promise in retaining the functional and physical traits of natural tissues observed at regions of craniofacial and dentoalveolar trauma or congenital defect while concomitantly ameliorating the risk of secondary infections, chronic pain, and other adverse effects that muddle the current index of treatments ( Birjandi et al, 2020 ; Zhang et al, 2020 ; Shang et al, 2021 ). With the intent of enhancing osteoblast proliferation and effectively regulating osteoclast activity, a growing number of studies assessing the use of small molecules on large defects of the mandibular, maxillofacial, periodontal, and dental tissues have succeeded in prompting the osteogenic repair through various models.…”

Wnt Signalling in Regenerative Dentistry

“…In vivo application of LiCl in rat molars results in higher β-catenin and a complete tertiary dentin (22). A number of small molecules that inhibit glycogen synthase kinase 3 (GSK3), a key enzyme in Wnt signalling pathway, have been shown to promote activation of Wnt pathway in vitro and dentin repair in mice and rats with experimental pulp exposures (23)(24)(25)(26). Treatment of dental pulp exposures with Semaphorin 3A, promotes formation of an odontoblastic layer, dentin tubules, and predentin (27).…”