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

Jeffrey K Holden; James J Crawford; Cameron L Noland; Stephen Schmidt; Jason R Zbieg; Jennifer A Lacap; Richard Zang; Gregory M Miller; Yue Zhang; Paul Beroza; Rohit Reja; Wendy Lee; Jeffrey Y K Tom; Rina Fong; Micah Steffek; Saundra Clausen; Thjis J Hagenbeek; Taishan Hu; Zheng Zhou; Hong C Shen; Christian N Cunningham

doi:10.1016/j.celrep.2020.107809

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.

Authors

Jeffrey K Holden¹, James J Crawford², Cameron L Noland³, Stephen Schmidt⁴, Jason R Zbieg², Jennifer A Lacap⁵, Richard Zang⁶, Gregory M Miller¹, Yue Zhang⁷, Paul Beroza², Rohit Reja⁷, Wendy Lee², Jeffrey Y K Tom¹, Rina Fong³, Micah Steffek⁴, Saundra Clausen⁴, Thjis J Hagenbeek⁸, Taishan Hu⁹, Zheng Zhou¹⁰, Hong C Shen⁹, Christian N Cunningham¹¹

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: [email protected].

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.

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

Substances

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