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The blood\u2012brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high\u2010resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c\u2010Myc. Additionally, von Hippel\u2012Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin\u2012proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.<\/jats:p>","DOI":"10.1002\/mco2.758","type":"journal-article","created":{"date-parts":[[2024,10,13]],"date-time":"2024-10-13T11:10:02Z","timestamp":1728817802000},"source":"Crossref","is-referenced-by-count":6,"title":["Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel\u2012Lindau tumor suppressor\u2010mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation"],"prefix":"10.1002","volume":"5","author":[{"given":"Fuyan","family":"Xu","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Oncology Frontiers Science Center for Disease\u2010Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University  Chengdu 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