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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
eLife, 10/2022, Letnik: 11Journal Article
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 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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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