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\/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-biorxiv-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 class=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article abstract-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EABSTRACT\u003C\/h2\u003E\u003Cp id=\u0022p-2\u0022\u003EAs the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP\/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true within the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors have shown great promise, but comparisons of their performances are so far limited. Here we develop a high content pipeline that enables a comparative analysis of currently developed YAP\/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer relevant assays in a clinically relevant cellular model.\u003C\/p\u003E\u003C\/div\u003E\u003Ch3\u003ECompeting Interest Statement\u003C\/h3\u003E\u003Cp id=\u0022p-3\u0022\u003EThe authors have declared no competing interest.\u003C\/p\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan class=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003Cdiv class=\u0022panel-separator\u0022\u003E\u003C\/div\u003E\u003Cdiv class=\u0022panel-pane pane-biorxiv-copyright\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022field field-name-field-highwire-copyright field-type-text field-label-inline clearfix\u0022\u003E\u003Cdiv class=\u0022field-label\u0022\u003ECopyright\u0026nbsp;\u003C\/div\u003E\u003Cdiv class=\u0022field-items\u0022\u003E\u003Cdiv class=\u0022field-item even\u0022\u003EThe copyright holder for this preprint is the author\/funder, who has granted bioRxiv a license to display the preprint in perpetuity.\u003Cspan class=\u0022license-type\u0022\u003E It is made available under a \u003Ca href=\u0022http:\/\/creativecommons.org\/licenses\/by\/4.0\/\u0022 class=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003ECC-BY 4.0 International license\u003C\/a\u003E.\u003C\/span\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/www.biorxiv.org\/sites\/default\/files\/js\/js_SXHPyYQMndPSjH0oAPTy1xd0XLtmYCIziRIiNb0RJd8.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}