2. Academic Validation
  3. Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling

Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling

  • Cell Rep. 2020 Jun 23;31(12):107809. doi: 10.1016/j.celrep.2020.107809.
Jeffrey K Holden 1,  James J Crawford 2,  Cameron L Noland 3,  Stephen Schmidt 4,  Jason R Zbieg 2,  Jennifer A Lacap 5,  Richard Zang 6,  Gregory M Miller 1,  Yue Zhang 7,  Paul Beroza 2,  Rohit Reja 7,  Wendy Lee 2,  Jeffrey Y K Tom 1,  Rina Fong 3,  Micah Steffek 4,  Saundra Clausen 4,  Thjis J Hagenbeek 8,  Taishan Hu 9,  Zheng Zhou 10,  Hong C Shen 9,  Christian N Cunningham 11
Affiliations

Affiliations

  • 1 Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA.
  • 2 Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 3 Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA.
  • 4 Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA.
  • 5 Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
  • 6 Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA.
  • 7 Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
  • 8 Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
  • 9 Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Shanghai 201203, People's Republic of China.
  • 10 Department of Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Shanghai 201203, People's Republic of China.
  • 11 Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA. Electronic address: cunningham.christian@gene.com.
PMID: 32579935 DOI: 10.1016/j.celrep.2020.107809
Abstract

The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model.

Keywords

Hippo pathway; TEAD; YAP; cancer; lipidation; therapeutic; transcription factor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-137479
    TEAD Autopalmitoylation Inhibitor
    YAP