In addition to mesothelioma, high level of nuclear YAP has been associated with poor prognosis in non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC) 3a. However, loss of function mutations in NF2 or LATS1/2, which occurs in >70% mesothelioma, promote YAP nuclear entry and binding with TEAD to drive oncogenesis 7. Tumor suppressor Merlin, encoded by NF2 gene, and kinase LATS1/2 are known upstream regulators that cooperatively promote phosphorylation of YAP and hence induce its retention and degradation in the cytoplasm 6. Tissue-specific deletion of the upstream regulators or overexpression of YAP itself results in hyperplasia, organ overgrowth and tumorigenesis 5. YAP has been well characterized as an oncoprotein 3 and its tumorigenesis role is mostly associated with TEAD mediated YAP-dependent gene expression 4. Importantly, TEADs alone show minimal transcriptional activity and require binding with a coactivator YAP/TAZ to initiate efficient gene expression 2. Critical components of Hippo signaling pathway are TEAD transcription factors, that are present as a family of four highly homologous members (TEAD1-4) in mammals. The Hippo pathway is a highly conserved signaling pathway that regulates embryonic development, organ size, cell proliferation, tissue regeneration, homeostasis and is responsible for the development and progression of many malignancies 1. 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. 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. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. 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. 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). Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. 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. 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. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway.
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