Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma
| Autor: | Sunil Kumar, Jacquelyn T Saunders, Angelica Benavides-Serrato, Brent Holmes, Joseph Gera, Robert N. Nishimura |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Antineoplastic Agents Apoptosis Article Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Animals Humans Molecular Targeted Therapy Transcription factor TEAD1 Adaptor Proteins Signal Transducing Cell Proliferation YAP1 Hippo signaling pathway Brain Neoplasms Activator (genetics) Chemistry Effector Nuclear Proteins TEA Domain Transcription Factors YAP-Signaling Proteins Xenograft Model Antitumor Assays DNA-Binding Proteins Neurology Oncology Hippo signaling Drug Design 030220 oncology & carcinogenesis Cancer research Neurology (clinical) Glioblastoma 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | J Neurooncol |
| ISSN: | 1573-7373 0167-594X |
| Popis: | INTRODUCTION: Recent studies have suggested that dysregulated Hippo pathway signaling may contribute to glioblastoma proliferation and invasive characteristics. The downstream effector of the pathway, the Yes-associated protein (YAP) oncoprotein, has emerged as a promising target in glioblastoma multiforme (GBM). METHODS: Utilizing a high-throughput yeast two-hybrid based screen, a small molecule was identified which inhibits the association of the co-transcriptional activator YAP1 and the TEA domain family member 1 (TEAD1) transcription factor protein–protein interaction interface. This candidate inhibitor, NSC682769, a novel benzazepine compound, was evaluated for its ability to affect Hippo/YAP axis signaling and potential anti-glioblastoma properties. RESULTS: NSC682769 potently blocked association of YAP and TEAD in vitro and in GBM cells treated with submicromolar concentrations. Moreover, inhibitor-coupled bead pull down and surface plasmon resonance analyses demonstrate that NSC682769 binds to YAP. NSC682769 treatment of GBM lines and patient derived cells resulted in downregulation of YAP expression levels resulting in curtailed YAP-TEAD transcriptional activity. In GBM cell models, NSC682769 inhibited proliferation, colony formation, migration, invasiveness and enhanced apoptosis. In tumor xenograft and genetically engineered mouse models, NSC682769 exhibited marked anti-tumor responses and resulted in increased overall survival and displayed significant blood-brain barrier penetration. CONCLUSIONS: These results demonstrate that blockade of YAP-TEAD association is a viable therapeutic strategy for glioblastoma. On the basis of these favorable preclinical studies further clinical studies are warranted. |
| Databáze: | OpenAIRE |
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