ArticleEMBO molecular medicine2016
Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy.
Article in EMBO molecular medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- Regenerative therapeutics for chronic obstructive pulmonary disease.Pharmacological reviews · 2026Review
- CircRNF10 sequestrates β-catenin by a dual regulatory circuit of direct degradation and a miR-1275/DKK3-mediated inhibition in driver gene- negative lung adenocarcinoma.Molecular cancer · 2025Article
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Signal integrator function of CXXC5 in Cancer.Cell communication and signaling : CCS · 2025Review
- Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease.Current cardiology reviews · 2025Review
- Review
- Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease.Bone research · 2024Review
- Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy.Journal of hematology & oncology · 2024Review
- FRZB affectsExperimental and therapeutic medicine · 2023Article
- A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities.Cells · 2023Review
- Aquaporin 9 is involved in CRC metastasis through DVL2-dependent Wnt/β-catenin signaling activation.Gastroenterology report · 2023Article
- Blockade of CXXC5-dishevelled interaction inhibits adipogenic differentiation, obesity, and insulin resistance in mice.Scientific reports · 2022Article
- Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment.Experimental & molecular medicine · 2022Article
- Inhibition of CXXC5 function reverses obesity-related metabolic diseases.Clinical and translational medicine · 2022Article
- Targeting the Wnt signaling pathway for breast cancer bone metastasis therapy.Journal of molecular medicine (Berlin, Germany) · 2022Review
- Understanding and utilizing textile-based electrostatic flocking for biomedical applications.Applied physics reviews · 2021Review
- Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer.Biology direct · 2021Review
- Ex vivo Bone Models and Their Potential in Preclinical Evaluation.Current osteoporosis reports · 2021Review
- Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling.Magnetic resonance (Gottingen, Germany) · 2021Article
- Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities.Molecular cancer · 2020Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.