Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor‐mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation

Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain 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‐resolution 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‐Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome 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. This study identifies penfluridol (PF) as a promising candidate for treating melanoma, particularly its brain metastases, by targeting and degrading CIP2A via the ubiquitin‒proteasome pathway. PF restores Protein Phosphatase 2A activity, inhibits key oncogenic pathways, and enhances the interaction between E3 ligase von Hippel‒Lindau and CIP2A, leading to reduced melanoma growth and metastasis in animal models.