CHSU Discovery

Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.

Journal of neuro-oncology Peer reviewed publication
volume 152 issue 2 pages 217-231
April 2021
DOI: 10.1007/s11060-021-03699-6 PMID: 33511508
EISSN: 1573-7373 ISSN: 0167-594X KBID: 2880 LN: Kumar CHSU: Faculty
  1. https://www.ncbi.nlm.nih.gov/pubmed/33511508
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005474/
  3. https://pubmed.ncbi.nlm.nih.gov/33511508
  4. https://doi.org/10.1007/s11060-021-03699-6

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Articles

Description

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.

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Subjects

Affiliations

  1. Department of Medicine, University of California, Los Angeles, CA, USA
  2. Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA
  3. Department of Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, CA, USA
  4. Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, 16111 Plummer Street (151), Building 1, Room C111A, Los Angeles, CA 91343, USA
  5. Jonnson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
  6. Molecular Biology Institute, University of California, Los Angeles, CA, USA

Publisher

Springer Nature (United States)

Languages

English

Citations

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