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

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.

Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP

“…The predicted inhibition mechanism of fisetin also resembled CPD3.1, that the compound could bind to the YAP-TEAD interaction interface and inhibit TEAD activity [80]. Binding of small molecules to the YAP-TEAD interface might also affect protein stability [81]. As demonstrated here that fisetin occupied the hydrophobic TEAD pocket; therefore, it suggests fisetin as a protein-protein interaction disruptor that disrupts the YAP-TEAD interaction and also suggesting an implication of fisetin for their therapeutic application.…”

Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator Inhibitor-1 (PAI-1) expression in hepatocarcinogenesis

“…Indeed, approaches for the activation of the Hippo pathway and especially the inactivation of its negatively regulated downstream effector YAP are currently intensely investigated. First recently presented small compounds developed by different companies have been proposed as potential lead-compounds since they change YAP reporter assays, directly disturb physical interaction between YAP and TEADs [25], or change TEAD activity in a dominant-negative manner [26]. Our results indicate, that alternative treatment strategies could focus on communication networks induced by YAP in tumorigenesis.…”

Design, Synthesis and Evaluation of a Series of 1,5‐Diaryl‐1,2,3‐triazole‐4‐carbohydrazones as Inhibitors of the YAP‐TAZ/TEAD Complex

“…Otherwise we could also have used a time-resolved fluorescence energy transfer (TR-FRET) assay and/or an immunoprecipitation assay of HEK293T cells co-transfected with TEAD2-FLAG and YAP-MYC to get complementary data of the YAP-TEAD disruptive potency of our compounds. [46] Finally a molecular docking study on our new hit 53 using two crystal structures of hTEAD2 (PDB code 5EMV and 5DQE) proposed two binding modes located on the external surface of hTEAD2 and on the interface 2 of hTEAD2, respectively. These results are in accordance with the nanoDSF study, in which our compounds (external TEAD binders) and niflumic acid (central palmitate pocket binder) displayed different TEAD denaturation profiles.…”