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Jie Zheng; Inhibitors of Dishevelled as a potential therapeutic approach for retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3157.
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© ARVO (1962-2015); The Authors (2016-present)
It was reported that in the proliferative oxygen-induced retinopathy mouse model, mutant mice lacking Dishevelled (Dvl), a key player in Wnt signaling pathways, showed significantly decreased neovascularization. Therefore, an inhibitor that targets Dvl may be able to block or reduce pathological vascular growth in proliferative retinopathy. In this study, we developed and test a set of small molecule inhibitors that can block Wnt signaling transduction by binding to the PDZ domain of Dvl and blocking the interaction between Dvl and Wnt-receptor Frizzled (Fz).
Previously, utilizing NMR spectroscopy, our laboratory determined the solution structure of the PDZ domain of Dvl and mapped the interface of the complex of Fz and Dvl PDZ domain. These structural findings provide a foundation for the current studies. Using structure-based virtual ligand screening and NMR spectroscopy, we identified several small-molecule inhibitors of Dvl. In addition, guided by the knowledge of the structural information of how those molecules interact with the Dvl PDZ domain, we further designed, synthesized, and tested additional novel inhibitors and showed that some of them interact with the PDZ domain of Dvl with high affinity. Moreover, using various assays, we tested their ability of specifically blocking Wnt signaling in vivo.
We successfully developed more than 80 small-molecule inhibitors of Dvl and showed that some of them interact with the PDZ domain of Dvl with low micromolar affinity. We selected the top 37 compounds and carried out a set of in vitro absorption, distribution, metabolism, and excretion (ADME) assays showing about 20 compounds have good drug-like properties. Using a luciferase-based assay, we tested these compounds and showed that they indeed inhibited Wnt signaling in 3T3 cells. Finally, we showed that these compounds could block Wnt signaling in a Xenopus-based assay. The studies of examining the effects of the best inhibitors on retinal neovascularization in different systems have been planned and the data will be reported in the presentation.
Our results showed that it is possible to inhibit Wnt signaling by using small molecule to block the Dvl PDZ domain and those inhibitors may potentially serve as novel pharmaceutical agents for treatment of eye diseases such as retinopathy of prematurity and proliferative diabetic retinopathy.
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