1. Biochemistry and Chemical Biology

Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode

  1. Lu Hu  Is a corresponding author
  2. Yang Sun
  3. Shun Liu
  4. Hannah Erb
  5. Alka Singh
  6. Junhao Mao
  7. Xuelian Luo  Is a corresponding author
  8. Xu Wu  Is a corresponding author
  1. Massachusetts General Hospital, United States
  2. The University of Texas Southwestern Medical Centerh, United States
  3. University of Massachusetts Medical School, United States
https://doi.org/10.7554/eLife.80210
Share this article
Cite this article
  1. Lu Hu
  2. Yang Sun
  3. Shun Liu
  4. Hannah Erb
  5. Alka Singh
  6. Junhao Mao
  7. Xuelian Luo
  8. Xu Wu
(2022)
Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode
eLife 11:e80210.
https://doi.org/10.7554/eLife.80210
  2. Download BibTeX
  3. Download .RIS

Abstract

The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers, and is associated with cancer cell proliferation, survival and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1-4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong anti-proliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency.

Data availability

The crystal structure of TEAD2 YBD in complex with TM2 has been deposited in the Protein Data Bank with accession codes 8CUH. The raw RNA-seq data of NCI-H226 treated with TM2, K975 and VT103 has been deposited in NCBI GEO and is accessible at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215114.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Lu Hu

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, United States
    For correspondence
    LHU8@mgh.harvard.edu
    Competing interests
    Lu Hu, is an inventor of a patent application covering TM2 and analogues as novel TEAD inhibitors..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1594-8828

  2. Yang Sun

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    No competing interests declared.

  3. Shun Liu

    Department of Pharmacology, The University of Texas Southwestern Medical Centerh, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1766-2057

  4. Hannah Erb

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    No competing interests declared.

  5. Alka Singh

    Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.

  6. Junhao Mao

    Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1980-1177

  7. Xuelian Luo

    Department of Pharmacology, The University of Texas Southwestern Medical Centerh, Dallas, United States
    For correspondence
    xuelian.luo@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5058-4695

  8. Xu Wu

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, United States
    For correspondence
    xwu@cbrc2.mgh.harvard.edu
    Competing interests
    Xu Wu, is an inventor of a patent application covering TM2 and analogues as novel TEAD inhibitors. Dr. Xu Wu has a financial interest in Tasca Therapuetics, which is developing small molecule modulators of TEAD palmitoylation and transcription factors. Dr. Wu's interests were reviewed and are managed by Mass General Hospital, and Mass General Brigham in accordance with their conflict of interest policies..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1624-0143

Funding

National Cancer Institute (R01CA219814)

  • Xu Wu

National Cancer Institute (R01CA238270)

  • Xu Wu

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127180)

  • Junhao Mao

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127207)

  • Junhao Mao

Welch Foundation (I-1932)

  • Xuelian Luo

Antidote Health Foundation for the cure of cancer (postdoc fellowship)

  • Lu Hu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Hu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,873
    views
  • 592
    downloads
  • 26
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Citations by DOI

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Lu Hu
  2. Yang Sun
  3. Shun Liu
  4. Hannah Erb
  5. Alka Singh
  6. Junhao Mao
  7. Xuelian Luo
  8. Xu Wu
(2022)
Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode
eLife 11:e80210.
https://doi.org/10.7554/eLife.80210

Share this article

https://doi.org/10.7554/eLife.80210

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology

    Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling

    Mengyang Fan, Wenchao Lu ... Nathanael S Gray
    Research Article Updated

    The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.