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.


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.

MeSH terms

  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Lipids / chemistry*
  • Lipoylation
  • Mice
  • Protein Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism
  • Signal Transduction* / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription Factors / agonists
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays


  • Lipids
  • Repressor Proteins
  • Small Molecule Libraries
  • Transcription Factors
  • Protein Serine-Threonine Kinases