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• W4282946415 abstract "ABSTRACT The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which play a critical role in cell proliferation, survival and cell fate specification. The core kinase cascade of the Hippo signaling pathway phosphorylates YAP/TAZ and restrict its activity by promoting cytoplasmic sequestration and degradation. Unphosphorylated YAP/TAZ translocates into the nucleus and associates with the TEA domain (TEAD1-4) transcription factors to regulate their target genes. They are frequently misregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention. However, due to their intrinsically disordered structure, they are challenging to target directly. Since YAP/TAZ exerts oncogenic activity by associating with the TEAD1-4 transcription factors, to regulate target gene expression, YAP activity can be controlled indirectly by regulating TEAD1-4. Interestingly, TEADs undergo autopalmitoylation, which is essential for their stability and function. The palmitic acid occupies a hydrophobic pocket in TEAD1-4, and small-molecule inhibitors that bind to this site can render them unstable, and allosterically inhibit their interaction with YAP/TAZ and chromatin. Here we combined structure-based virtual ligand screening with biochemical and cell biological studies and identified a novel small-molecule that inhibits TEAD palmitoylation and stability. Further, it affects YAP-TEAD interaction and inhibits YAP transcriptional activity and impairs proliferation, colony formation and migration of breast and ovarian cancer cells." @default.
• W4282946415 created "2022-06-16" @default.
• W4282946415 creator A5004101565 @default.
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• W4282946415 date "2022-06-11" @default.
• W4282946415 modified "2023-09-28" @default.
• W4282946415 title "Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity" @default.
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• W4282946415 doi "https://doi.org/10.1101/2022.06.09.495565" @default.
• W4282946415 hasPublicationYear "2022" @default.
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