1. Academic Validation
  2. Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma

Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma

  • Mol Cancer Ther. 2021 Jun;20(6):986-998. doi: 10.1158/1535-7163.MCT-20-0717.
Tracy T Tang  # 1 Andrei W Konradi  # 2 Ying Feng 2 Xiao Peng 2 Mingyue Ma 3 Jian Li 3 Fa-Xing Yu 3 Kun-Liang Guan 4 Leonard Post 2
Affiliations

Affiliations

  • 1 Vivace Therapeutics, Inc., San Mateo, California. ttang@vivacetherapeutics.com.
  • 2 Vivace Therapeutics, Inc., San Mateo, California.
  • 3 Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 4 Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California.
  • # Contributed equally.
Abstract

Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in Other YAP-driven cancers and diseases.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134956
    99.94%, YAP/TAZ抑制剂
    YAP
  • HY-134957
    99.89%, pan-TEAD Auto-Palmitoylation抑制剂
    YAP
  • HY-134955
    99.64%, TEAD1棕榈酰化抑制剂
    YAP
  • HY-163644
    99.93%, YAP 抑制剂
    YAP
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