Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine.
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TLDR
A review of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein-protein interaction (PPI) with TEAD1-4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP 1/TZ-dependent transcription in cancer as mentioned in this paper.Abstract:
The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.read more
Citations
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The Hippo signalling pathway and its implications in human health and diseases
TL;DR: The Hippo pathway plays a crucial role in the regulation of numerous biological processes, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing as discussed by the authors .
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Regulation of Hippo signaling by metabolic pathways in cancer.
TL;DR: In this article , an integrated perspective of the relationship between the Hippo signaling pathway and metabolic signals in the context of cancer is described. And several novel targets for anticancer drug treatment are proposed.
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YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches
Journal ArticleDOI
The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition
Pascal Furet,Vincent Bordas,Mickaël Le Douget,Bahaa Salem,Yannick Mesrouze,Patricia Imbach-Weese,Holger Sellner,Markus Voegtle,Nicolas Soldermann,Emilie A. Chapeau,Markus Wartmann,Clemens Scheufler,Cesar A. Pena Fernandez,Joerg Kallen,Vito Guagnano,Patrick Chène,Tobias Schmelzle +16 more
TL;DR: The discovery of the first class of small molecules potently inhibiting the YAP‐TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD is disclosed.
Journal ArticleDOI
Therapeutic targeting of TEAD transcription factors in cancer.
TL;DR: A review of the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TAD inhibitors as mentioned in this paper .
References
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Oncogenic Signaling Pathways in The Cancer Genome Atlas
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The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP
TL;DR: Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), is identified as a missing link between Wts and transcriptional regulation and is a critical target of the Wts/Lats protein kinase and a potential oncogene.
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YAP/TAZ at the Roots of Cancer
TL;DR: In this paper, a number of cancer-associated extrinsic and intrinsic cues conspire to overrule the YAP-inhibiting microenvironment of normal tissues, including changes in mechanotransduction, inflammation, oncogenic signaling, and regulation of the Hippo pathway.