Jacquelyn T Saunders1,2, Brent Holmes1,2, Angelica Benavides-Serrato1,2, Sunil Kumar3,2, Robert N Nishimura4,2, Joseph Gera5,6,7,8. 1. Department of Medicine, University of California, Los Angeles, CA, USA. 2. Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, 16111 Plummer Street (151), Building 1, Room C111A, Los Angeles, CA, 91343, USA. 3. Department of Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, CA, USA. 4. Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA. 5. Department of Medicine, University of California, Los Angeles, CA, USA. jgera@mednet.ucla.edu. 6. Jonnson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. jgera@mednet.ucla.edu. 7. Molecular Biology Institute, University of California, Los Angeles, CA, USA. jgera@mednet.ucla.edu. 8. Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, 16111 Plummer Street (151), Building 1, Room C111A, Los Angeles, CA, 91343, USA. jgera@mednet.ucla.edu.
Abstract
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.
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.
Entities:
Keywords:
Glioblastoma; Hippo signaling; Small molecule inhibitor; TEAD; YAP
Authors: Krishna P L Bhat; Katrina L Salazar; Veerakumar Balasubramaniyan; Khalida Wani; Lindsey Heathcock; Faith Hollingsworth; Johanna D James; Joy Gumin; Kristin L Diefes; Se Hoon Kim; Alice Turski; Yasaman Azodi; Yuhui Yang; Tiffany Doucette; Howard Colman; Erik P Sulman; Frederick F Lang; Ganesh Rao; Sjef Copray; Brian D Vaillant; Kenneth D Aldape Journal: Genes Dev Date: 2011-12-15 Impact factor: 11.361