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Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling.
| Content Provider | Europe PMC |
|---|---|
| Author | Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit 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 Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S |
| Editor | Pan, Duojia Struhl, Kevin |
| Copyright Year | 2022 |
| 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. |
| Journal | eLife |
| Volume Number | 11 |
| PubMed Central reference number | PMC9728995 |
| PubMed reference number | 36300789 |
| e-ISSN | 2050084X |
| DOI | 10.7554/elife.78810 |
| Language | English |
| Publisher | eLife Sciences Publications, Ltd |
| Publisher Date | 2022-10-27 |
| Access Restriction | Open |
| Rights License | This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2022, Fan, Lu et al |
| Subject Keyword | YAP TEAD palmitoylation covalent ligand transcription factors mesothelioma Human |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology |
