{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:04:36Z","timestamp":1789362276824,"version":"build-2803163510"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"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>Aberrant activation of the Hippo\u2013YAP\/TAZ\u2013TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP\u2013TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690\/36549045, AN-655\/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP\u2013TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP\u2013TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.<\/jats:p>","DOI":"10.3389\/fonc.2026.1908974","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:36:53Z","timestamp":1789360613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Experimental assessment of computationally nominated small molecules targeting the YAP\u2013TEAD interface in Hippo pathway-altered mesothelioma cell models"],"prefix":"10.3389","volume":"16","author":[{"given":"Glen J.","family":"Weiss","sequence":"first","affiliation":[{"name":"International Genomics Consortium","place":["Phoenix, AZ, United States"]},{"name":"Department of Medicine, UMass Chan Medical School","place":["Worcester, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Loftus","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Mayo Clinic Arizona","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Mallery","sequence":"additional","affiliation":[{"name":"International Genomics Consortium","place":["Phoenix, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhan L.","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Immunology and Microbiome, Translational Genomics Research Institute","place":["Phoenix, AZ, United States"]},{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope","place":["Duarte, CA, United 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