title: Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy.
abstract: Bone anabolic agents promoting bone formation and rebuilding damaged bones would ideally overcome the limitations of anti-resorptive therapy, the current standard prescription for osteoporosis. However, the currently prescribed parathyroid hormone (PTH)-based anabolic drugs present limitations and adverse effects including osteosarcoma during long-term use. Also, the antibody-based anabolic drugs that are currently being developed present the potential limits in clinical application typical of macromolecule drugs. We previously identified that CXXC5 is a negative feedback regulator of the Wnt/β-catenin pathway via its interaction with Dishevelled (Dvl) and suggested the Dvl-CXXC5 interaction as a potential target for anabolic therapy of osteoporosis. Here, we screened small-molecule inhibitors of the Dvl-CXXC5 interaction via a newly established in vitro assay system. The screened compounds were found to activate the Wnt/β-catenin pathway and enhance osteoblast differentiation in primary osteoblasts. The bone anabolic effects of the compounds were shown using ex vivo-cultured calvaria. Nuclear magnetic resonance (NMR) titration analysis confirmed interaction between Dvl PDZ domain and KY-02061, a representative of the screened compounds. Oral administration of KY-02327, one of 55 newly synthesized KY-02061 analogs, successfully rescued bone loss in the ovariectomized (OVX) mouse model. In conclusion, small-molecule inhibitors of the Dvl-CXXC5 interaction that block negative feedback regulation of Wnt/β-catenin signaling are potential candidates for the development of bone anabolic anti-osteoporosis drugs.
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea Department of Biotechnology, College of Life Science and Biotechnology Yonsei University, Seoul, Korea.
authors.forename: Hyun-Yi
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea Department of Biotechnology, College of Life Science and Biotechnology Yonsei University, Seoul, Korea.
authors.forename: Sehee
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology Yonsei University, Seoul, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Hwan Jung
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Lee
authors.affiliation: Bioinformatics & Molecular Design Research Center, Yonsei University, Seoul, Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea Department of Biotechnology, College of Life Science and Biotechnology Yonsei University, Seoul, Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Ro
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Jung-Nyoung
authors.initials: JN
authors.lastname: Heo
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology Yonsei University, Seoul, Korea.
authors.forename: Weontae
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology Yonsei University, Seoul, Korea Bioinformatics & Molecular Design Research Center, Yonsei University, Seoul, Korea.
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea Department of Biotechnology, College of Life Science and Biotechnology Yonsei University, Seoul, Korea kychoi@yonsei.ac.kr.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy*; D011485:Protein Binding / Q000187:drug effects; D012886:Skull / Q000187:drug effects / Q000254:growth & development; D014157:Transcription Factors; D016896:Treatment Outcome; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C000601091:CXXC5 protein, mouse; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors
keywords: CXXC5; Dishevelled; Wnt/β‐catenin pathway; negative feedback regulation; osteoporosis