{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T08:20:41Z","timestamp":1793521241314,"version":"4.5.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which plays a critical role in cell proliferation, survival and cell fate specification. They are frequently deregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo\/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention. However, due to their intrinsically disordered structure, they are challenging to target directly. Since YAP\/TAZ exerts oncogenic activity by associating with the TEAD1-4 transcription factors, to regulate target gene expression, YAP activity can be controlled indirectly by regulating TEAD1-4. Interestingly, TEADs undergo autopalmitoylation, which is essential for their stability and function, and small-molecule inhibitors that prevent this posttranslational modification can render them unstable. In this article we report discovery of a novel small molecule inhibitor of YAP activity. We combined structure-based virtual ligand screening with biochemical and cell biological studies and identified JM7, which inhibits YAP transcriptional reporter activity with an IC50 of 972 nMoles\/Ltr. Further, it inhibits YAP target gene expression, without affecting YAP\/TEAD localization. Mechanistically, JM7 inhibits TEAD palmitoylation and renders them unstable. Cellular thermal shift assay revealed that JM7 directly binds to TEAD1-4 in cells. Consistent with the inhibitory effect of JM7 on YAP activity, it significantly impairs proliferation, colony-formation and migration of mesothelioma (NCI-H226), breast (MDA-MB-231) and ovarian (OVCAR-8) cancer cells that exhibit increased YAP activity. Collectively, these results establish JM7 as a novel lead compound for development of more potent inhibitors of TEAD palmitoylation for treating cancer.<\/jats:p>","DOI":"10.3389\/fonc.2022.1021823","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T03:37:27Z","timestamp":1669693047000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity"],"prefix":"10.3389","volume":"12","author":[{"given":"Artem","family":"Gridnev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhajit","family":"Maity","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti R.","family":"Misra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-120417-031621","article-title":"The hippo signaling network and its biological functions","volume":"52","author":"Misra","year":"2018","journal-title":"Annu Rev Genet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1146\/annurev-biochem-013118-111829","article-title":"The hippo pathway: Biology and pathophysiology","volume":"88","author":"Ma","year":"2019","journal-title":"Annu Rev Biochem"},{"key":"B3","doi-asserted-by":"publisher","first-page":"8357","DOI":"10.1038\/ncomms9357","article-title":"MAP4K family kinases act in parallel to MST1\/2 to activate LATS1\/2 in the hippo pathway","volume":"6","author":"Meng","year":"2015","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.molcel.2016.10.034","article-title":"Characterization of hippo pathway components by gene inactivation","volume":"64","author":"Plouffe","year":"2016","journal-title":"Mol Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.15698\/cst2021.11.258","article-title":"Mechanisms of YAP\/TAZ transcriptional control","volume":"5","author":"Battilana","year":"2021","journal-title":"Cell Stress"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4242","DOI":"10.3390\/cancers13164242","article-title":"Emerging principles in the transcriptional control by YAP and TAZ","volume":"13","author":"Lopez-Hernandez","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0168-y","article-title":"YAP and TAZ: a signalling hub of the tumour microenvironment","volume":"19","author":"Zanconato","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0070-z","article-title":"Targeting the hippo pathway in cancer, fibrosis, wound healing and regenerative medicine","volume":"19","author":"Dey","year":"2020","journal-title":"Nat Rev Drug Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.025","article-title":"Spatial organization of hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin\/NF2","volume":"154","author":"Yin","year":"2013","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.125","article-title":"Role of Merlin\/NF2 inactivation in tumor biology","volume":"35","author":"Petrilli","year":"2016","journal-title":"Oncogene"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative molecular characterization of malignant pleural mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discovery"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.3390\/cancers11111633","article-title":"The role of Merlin\/NF2 loss in meningioma biology","volume":"11","author":"Lee","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"137","DOI":"10.3390\/cancers10050137","article-title":"YAP and TAZ in lung cancer: Oncogenic role and clinical targeting","volume":"10","author":"Lo Sardo","year":"2018","journal-title":"Cancers (Basel)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e62857","DOI":"10.7554\/eLife.62857.sa2","article-title":"TAZ-CAMTA1 and YAP-TFE3 alter the TAZ\/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex","volume":"10","author":"Merritt","year":"2021","journal-title":"eLife"},{"key":"B16","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1101\/gad.348221.120","article-title":"WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma","volume":"35","author":"Driskill","year":"2021","journal-title":"Genes Dev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1101\/gad.348220.120","article-title":"WWTR1(TAZ)-CAMTA1 gene fusion is sufficient to dysregulate YAP\/TAZ signaling and drive epithelioid hemangioendothelioma tumorigenesis","volume":"35","author":"Seavey","year":"2021","journal-title":"Genes Dev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.148","article-title":"Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein","volume":"35","author":"Tanas","year":"2016","journal-title":"Oncogene"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1016\/j.molcel.2021.01.010","article-title":"Interferon-gamma induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation","volume":"81","author":"Yu","year":"2021","journal-title":"Mol Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0485-0","article-title":"Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression","volume":"22","author":"Lu","year":"2020","journal-title":"Nat Cell Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0433-z","article-title":"Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression","volume":"21","author":"Cai","year":"2019","journal-title":"Nat Cell Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2019.02.010","article-title":"YAP\/TAZ signaling and resistance to cancer therapy","volume":"5","author":"Nguyen","year":"2019","journal-title":"Trends Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"83","DOI":"10.14348\/molcells.2018.2242","article-title":"The role of hippo pathway in cancer stem cell biology","volume":"41","author":"Park","year":"2018","journal-title":"Mol Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1158\/2159-8290.CD-15-0224","article-title":"Targeting YAP-dependent MDSC infiltration impairs tumor progression","volume":"6","author":"Wang","year":"2016","journal-title":"Cancer Discov"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1124","article-title":"YAP is essential for treg-mediated suppression of antitumor immunity","volume":"8","author":"Ni","year":"2018","journal-title":"Cancer Discov"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0320","article-title":"YAP-induced PD-L1 expression drives immune evasion in BRAFi-resistant melanoma","volume":"6","author":"Kim","year":"2018","journal-title":"Cancer Immunol Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.23051","article-title":"YAP regulates PD-L1 expression in human NSCLC cells","volume":"8","author":"Miao","year":"2017","journal-title":"Oncotarget"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.07.007","article-title":"Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma","volume":"491","author":"Lee","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.3390\/cells10102715","article-title":"Recent therapeutic approaches to modulate the hippo pathway in oncology and regenerative medicine","volume":"10","author":"Barry","year":"2021","journal-title":"Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6001","DOI":"10.3390\/molecules25246001","article-title":"Protein-protein interaction disruptors of the YAP\/TAZ-TEAD transcriptional complex","volume":"25","author":"Pobbati","year":"2020","journal-title":"Molecules"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01402","article-title":"Antiproliferative and antimigratory effects of a novel YAP-TEAD interaction inhibitor identified using in silico molecular docking","volume":"62","author":"Smith","year":"2019","journal-title":"J Med Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2036","article-title":"Autopalmitoylation of TEAD proteins regulates transcriptional output of the hippo pathway","volume":"12","author":"Chan","year":"2016","journal-title":"Nat Chem Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.11.005","article-title":"Palmitoylation of TEAD transcription factors is required for their stability and function in hippo pathway signaling","volume":"24","author":"Noland","year":"2016","journal-title":"Structure"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-20-0717","article-title":"Small molecule inhibitors of TEAD auto-palmitoylation selectively inhibit proliferation and tumor growth of NF2-deficient mesothelioma","volume":"20","author":"Tang","year":"2021","journal-title":"Mol Cancer Ther"},{"key":"B35","doi-asserted-by":"publisher","first-page":"107809","DOI":"10.1016\/j.celrep.2020.107809","article-title":"Small molecule dysregulation of TEAD lipidation induces a dominant-negative inhibition of hippo pathway signaling","volume":"31","author":"Holden","year":"2020","journal-title":"Cell Rep"},{"key":"B36","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.chembiol.2018.11.010","article-title":"Small-molecule covalent modification of conserved cysteine leads to allosteric inhibition of the TEADYap protein-protein interaction","volume":"26","author":"Bum-Erdene","year":"2019","journal-title":"Cell Chem Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2117-z","article-title":"An open-source drug discovery platform enables ultra-large virtual screens","volume":"580","author":"Gorgulla","year":"2020","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04220-9","article-title":"Synthon-based ligand discovery in virtual libraries of over 11 billion compounds","volume":"601","author":"Sadybekov","year":"2021","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00597-z","article-title":"A practical guide to large-scale docking","volume":"16","author":"Bender","year":"2021","journal-title":"Nat Protoc"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.3390\/cancers11101596","article-title":"Identification of celastrol as a novel YAP-TEAD inhibitor for cancer therapy by high throughput screening with ultrasensitive YAP\/TAZ-TEAD biosensors","volume":"11","author":"Nouri","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.138","article-title":"The cellular thermal shift assay for evaluating drug target interactions in cells","volume":"9","author":"Jafari","year":"2014","journal-title":"Nat Protoc"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00075","article-title":"Toward the design of ligands selective for the c-terminal domain of TEADs","volume":"65","author":"Liberelle","year":"2022","journal-title":"J Med Chem"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00403","article-title":"Optimization of TEAD p-site binding fragment hit into In vivo active lead MSC-4106","volume":"65","author":"Heinrich","year":"2022","journal-title":"J Med Chem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-4179","article-title":"Yap1 mediates trametinib resistance in head and neck squamous cell carcinomas","volume":"27","author":"Mudianto","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.3390\/cancers12051108","article-title":"The hippo pathway transducers YAP1\/TEAD induce acquired resistance to trastuzumab in HER2-positive breast cancer","volume":"12","author":"Gonzalez-Alonso","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2668","article-title":"YAP1 promotes multidrug resistance of small cell lung cancer by CD74-related signaling pathways","volume":"9","author":"Song","year":"2020","journal-title":"Cancer Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz4589","article-title":"A YAP\/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components","volume":"12","author":"Nilsson","year":"2020","journal-title":"Sci Trans Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-1415","article-title":"YAP1 mediates resistance to MEK1\/2 inhibition in neuroblastomas with hyperactivated RAS signaling","volume":"79","author":"Coggins","year":"2019","journal-title":"Cancer Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3218","article-title":"The hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies","volume":"47","author":"Lin","year":"2015","journal-title":"Nat Genet"},{"key":"B51","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41467-019-13771-5","article-title":"YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation","volume":"11","author":"Tsuji","year":"2020","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1172\/JCI93561","article-title":"Mechanosensing and fibrosis","volume":"128","author":"Tschumperlin","year":"2018","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1021823\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T03:37:31Z","timestamp":1669693051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1021823\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,29]]},"references-count":52,"alternative-id":["10.3389\/fonc.2022.1021823"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.1021823","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.06.09.495565","asserted-by":"object"}]},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,29]]},"article-number":"1021823"}}