Bone anabolic agents promoting bone formation and rebuilding\ndamaged bones would ideally overcome the limitations of antiresorptive\ntherapy, the current standard prescription for\nosteoporosis. However, the currently prescribed parathyroid\nhormone (PTH)-based anabolic drugs present limitations and\nadverse effects including osteosarcoma during long-term use. Also,\nthe antibody-based anabolic drugs that are currently being developed\npresent the potential limits in clinical application typical of\nmacromolecule drugs. We previously identified that CXXC5 is a\nnegative feedback regulator of the Wnt/b-catenin pathway via its\ninteraction with Dishevelled (Dvl) and suggested the Dvlââ?¬â??CXXC5\ninteraction as a potential target for anabolic therapy of osteoporosis.\nHere, we screened small-molecule inhibitors of the Dvlââ?¬â??CXXC5\ninteraction via a newly established in vitro assay system. The\nscreened compounds were found to activate the Wnt/b-catenin\npathway and enhance osteoblast differentiation in primary osteoblasts.\nThe bone anabolic effects of the compounds were shown\nusing ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR)\ntitration analysis confirmed interaction between Dvl PDZ domain\nand KY-02061, a representative of the screened compounds. Oral\nadministration of KY-02327, one of 55 newly synthesized KY-02061\nanalogs, successfully rescued bone loss in the ovariectomized\n(OVX) mouse model. In conclusion, small-molecule inhibitors of the\nDvlââ?¬â??CXXC5 interaction that block negative feedback regulation of\nWnt/b-catenin signaling are potential candidates for the\ndevelopment of bone anabolic anti-osteoporosis drugs.
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