2. Academic Validation
  3. Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma

Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma

  • Life Sci Alliance. 2025 Jul 31;8(10):e202503241. doi: 10.26508/lsa.202503241.
Richard Cunningham 1,  Siyang Jia 1,  Krishna Purohit 1,  Michaela Noskova Fairley 1,  Marcin K Maniak 1,  Yue Lin 1,  Ning Sze Hui 1,  Rebecca E Graham 2,  Adriano G Rossi 1,  Justyna Cholewa-Waclaw 3,  Pierre O Bagnaninchi 4,  Neil O Carragher 5,  Carsten Gram Hansen 6
Affiliations

Affiliations

  • 1 Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, BioQuarter, Edinburgh, UK.
  • 2 Centre for Clinical Brain Sciences, Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK.
  • 3 High Content Screening Facility, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
  • 4 Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
  • 5 Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
  • 6 Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, BioQuarter, Edinburgh, UK Carsten.G.Hansen@ed.ac.uk.
PMID: 40744733 DOI: 10.26508/lsa.202503241
Abstract

As 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 in 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 has 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 of pleural mesothelioma.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138565
    99.89%, YAP1/TAZ-TEAD Inhibitor
    YAP
  • HY-134957
    99.89%, pan-TEAD Auto-Palmitoylation Inhibitor
    YAP