Covalent disruptor of YAP-TEAD association suppresses defective hippo signaling
- Dana-Farber Cancer Institute, United States
- Stanford University, United States
- Broad Institute, United States
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".
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Supplementary dataset 1: Proteome-wide selectivity profile of MYF-03-69 on cysteines labeling using SLC-ABPP approachDryad Digital Repository, doi:10.5061/dryad.rxwdbrvbn.
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Supplementary Dataset 2. List of differentially expressed genes under MYF-03-69 treatmentsDryad Digital Repository, doi:10.5061/dryad.sn02v6x6g.
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Supplementary Dataset 3. Area under the curve (AUC) data of PRISM cell viability screen and corresponding CERES scores of YAP1 and TEADsDryad Digital Repository, doi:10.5061/dryad.3r2280gjk.
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Supplementary Dataset 4. Correlation analysis of MYF-03-69 PRISM sensitivity profile and gene DepMap dependency scoresDryad Digital Repository, doi:10.5061/dryad.kh189327w.
Article and author information
Author details
Andrew S Boghossian
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.
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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Covalent disruptor of YAP-TEAD association suppresses defective hippo signaling
eLife 11:e78810.
https://doi.org/10.7554/eLife.78810
Further reading
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- Biochemistry and Chemical Biology
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Teichoic acids (TA) are linear phospho-saccharidic polymers and important constituents of the cell envelope of Gram-positive bacteria, either bound to the peptidoglycan as wall teichoic acids (WTA) or to the membrane as lipoteichoic acids (LTA). The composition of TA varies greatly but the presence of both WTA and LTA is highly conserved, hinting at an underlying fundamental function that is distinct from their specific roles in diverse organisms. We report the observation of a periplasmic space in Streptococcus pneumoniae by cryo-electron microscopy of vitreous sections. The thickness and appearance of this region change upon deletion of genes involved in the attachment of TA, supporting their role in the maintenance of a periplasmic space in Gram-positive bacteria as a possible universal function. Consequences of these mutations were further examined by super-resolved microscopy, following metabolic labeling and fluorophore coupling by click chemistry. This novel labeling method also enabled in-gel analysis of cell fractions. With this approach, we were able to titrate the actual amount of TA per cell and to determine the ratio of WTA to LTA. In addition, we followed the change of TA length during growth phases, and discovered that a mutant devoid of LTA accumulates the membrane-bound polymerized TA precursor.
