Abstract

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.

Data availability

Diffraction data have been deposited in PDB under the accession code 7LI5.RNA sequencing data have been deposited in BioSample database under accession codes SAMN19288936, SAMN19288937, SAMN19288938, SAMN19288939, SAMN19288940, SAMN19288941, SAMN19288942, SAMN19288943, SAMN19288944, SAMN19288945 and SAMN19288946.All datasets generated or analyzed during this study have been deposited in Dryad.Uncropped gels or blots image of Figure 1e, 2e, 3a, 3b, 4d and their related figure supplement 3, 4, 7 were provided in the zipped folder "Source data files".

The following data sets were generated

Article and author information

Author details

  1. Mengyang Fan

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Mengyang Fan, is one of the inventors on TEAD inhibitor patents (WO2020081572A1).
  2. Wenchao Lu

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1175-365X
  3. Jianwei Che

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Jianwei Che, is a consultant to Soltego, Jengu, Allorion, EoCys, and equity holder for Soltego, Allorion, EoCys, and M3 bioinformatics & technology Inc..
  4. Nicholas P Kwiatkowski

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Yang Gao

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Yang Gao, is one of the inventors on TEAD inhibitor patents (WO2020081572A1).
  6. Hyuk-Soo Seo

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  7. Scott B Ficarro

    Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Prafulla C Gokhale

    Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  9. Yao Liu

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Yao Liu, is one of the inventors on TEAD inhibitor patents (WO2020081572A1).
  10. Ezekiel A Geffken

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Jimit Lakhani

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Kijun Song

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6037-9345
  13. Miljan Kuljanin

    Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  14. Wenzhi Ji

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  15. Jie Jiang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3795-672X
  16. Zhixiang He

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Jason Tse

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  18. Andrew S Boghossian

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7008-8138
  19. Matthew G Rees

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  20. Melissa M Ronan

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  21. Jennifer A Roth

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  22. Joseph D Mancias

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  23. Jarrod A Marto

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  24. Sirano Dhe-Paganon

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  25. Tinghu Zhang

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    For correspondence
    ztinghu8@stanford.edu
    Competing interests
    Tinghu Zhang, is a consultant and equity holder of EoCys and is one of the inventors on TEAD inhibitor patents (WO2020081572A1)..
  26. Nathanael S Gray

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    For correspondence
    nsgray01@stanford.edu
    Competing interests
    Nathanael S Gray, is a founder, science advisory board (SAB) member and equity holder in Syros, Jengu, C4, B2S, Allorion, Inception, GSK, Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Interline, Springworks and Sanofi. TEAD inhibitors developed in this manuscript are licensed to a start-up ( Lighthorse) where Gray has a financial interest. N.S.G. is one of the inventors on TEAD inhibitor patents (WO2020081572A1)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403

Funding

The Gray lab has sponsored research agreement for TEAD inhibitor project with Epiphanes. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals acclimated for at least 5 days before initiation of the study. All in vivo studies were conducted at Dana-Farber Cancer Institute with the approval of the Institutional Animal Care and Use Committee in an AAALAC accredited vivarium.

Reviewing Editor

  1. Duojia Pan, UT Southwestern Medical Center and HHMI, United States

Version history

  1. Received: March 21, 2022
  2. Preprint posted: May 11, 2022 (view preprint)
  3. Accepted: October 26, 2022
  4. Accepted Manuscript published: October 27, 2022 (version 1)
  5. Version of Record published: December 7, 2022 (version 2)

Copyright

© 2022, Fan 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.

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  1. Mengyang Fan
  2. Wenchao Lu
  3. Jianwei Che
  4. Nicholas P Kwiatkowski
  5. Yang Gao
  6. Hyuk-Soo Seo
  7. Scott B Ficarro
  8. Prafulla C Gokhale
  9. Yao Liu
  10. Ezekiel A Geffken
  11. Jimit Lakhani
  12. Kijun Song
  13. Miljan Kuljanin
  14. Wenzhi Ji
  15. Jie Jiang
  16. Zhixiang He
  17. Jason Tse
  18. Andrew S Boghossian
  19. Matthew G Rees
  20. Melissa M Ronan
  21. Jennifer A Roth
  22. Joseph D Mancias
  23. Jarrod A Marto
  24. Sirano Dhe-Paganon
  25. Tinghu Zhang
  26. Nathanael S Gray
(2022)
Covalent disruptor of YAP-TEAD association suppresses defective hippo signaling
eLife 11:e78810.
https://doi.org/10.7554/eLife.78810

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