Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
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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.
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MYF-03-69 is a tool compound that covalently binds the conserved TEAD palmitate pocket, irreversibly disrupting YAP-TEAD association and suppressing TEAD1-4 transcriptional activity.
“MYF-03-69 is a tool compound that binds covalently to the conserved TEAD palmitate pocket, irreversibly disrupting YAP-TEAD association and suppressing TEAD1-4 transcriptional activity (48).”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [48]
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- Authors
- Fan, M., Lu, W., Che, J., Kwiatkowski, N. P., Gao, Y., Seo, H.-S., Ficarro, S. B., Gokhale, P. C., Liu, Y., Geffken, E. A., Lakhani, J., Song, K., Kuljanin, M., Ji, W., Jiang, J., He, Z., Tse, J., Boghossian, A. S., Rees, M. G., Ronan, M. M., Roth, J. A., Mancias, J. D., Marto, J. A., Dhe-Paganon, S., Zhang, T., & Gray, N. S.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Stanford Medicine (US)
- Broad Institute (US)
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School
- Corresponding author
- Zhang, Tinghu
- Gray, Nathanael S
- ORCID
- Fan, Mengyang
- Lu, Wenchao
- Che, Jianwei
- Kwiatkowski, Nicholas P
- Gao, Yang
- Seo, Hyuk-Soo
- Ficarro, Scott B
- Gokhale, Prafulla C
- Liu, Yao
- Song, Kijun
- Kuljanin, Miljan
- Ji, Wenzhi
- Jiang, Jie
- He, Zhixiang
- Tse, Jason
- Boghossian, Andrew S
- Rees, Matthew G
- Ronan, Melissa M
- Roth, Jennifer A
- Mancias, Joseph D
- Marto, Jarrod A
- Zhang, Tinghu
- Gray, Nathanael S
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-10-27
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9728995
- OpenAlex
- W4307366576
- Cited by
- 68
- References
- 59
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 21 · 2023: 14 · 2020: 1
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Epiphanes
- Hale Family Center for Pancreatic Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- TEAD, YAP, Hippo signaling pathway, covalent inhibitors, palmitoylation, malignant pleural mesothelioma, BMF, structure-based drug design
- MeSH terms
- Hippo Signaling Pathway, Animals, Cysteine, Humans, Research Design, Transplantation, Heterologous, Transcriptional Activation, Mice
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