Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models

Our plain-English summary of Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models, by G.J. Weiss, J.C. Loftus, D.W. Mallery, et al (Frontiers in Oncology, 2026).

The study

• Authors: G.J. Weiss, J.C. Loftus, D.W. Mallery, N.L. Tran
• Journal: Frontiers in Oncology
• Published: 2026;16:1908974
• Read it: PubMed · Publisher · Free full text

Abstract

Aberrant activation of the Hippo-YAP/TAZ-TEAD 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-TEAD 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-TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP-TEAD 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.

Copyright © 2026 Weiss, Loftus, Mallery and Tran.

In plain English

This laboratory study tested small molecules that a computer-based (in silico) screen had nominated as possible blockers of the YAP–TEAD protein interface. The authors noted that loss-of-function alterations in NF2 or LATS1/2 occur at high frequency in malignant pleural mesothelioma and confer strong dependence on YAP/TAZ-mediated transcriptional output. Starting from the crystal structure of the human YAP–TEAD complex, the authors docked about 917,000 library compounds into three predicted binding sites, then tested a small number of the top candidates in cells. In 144-hour CellTiter-Glo proliferation assays in three Hippo-altered mesothelioma cell lines, the reference TEAD inhibitor K-975 gave approximate IC50 values of about 45 nM in MSTO-211H and about 85 nM in NCI-H2052, with greater than 2,000 nM in NCI-H226. The nominated compounds AG-690/36549045 and AN-655/40856217 showed no measurable activity (greater than 2,000 nM) in all three lines. In an exploratory TEAD reporter in MCF7 cells, falls in reporter signal tracked with loss of cell viability. The authors concluded that computational nomination showed limited concordance with cell-based activity, and reported these negative findings transparently.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro experimental study: structure-guided computational virtual screening followed by cell-based proliferation, apoptosis and reporter assays (no human or animal subjects)
• Who was studied: Three human malignant pleural mesothelioma cell lines (MSTO-211H, LATS1/2-deficient; NCI-H2052, NF2-deficient; NCI-H226, NF2-deficient) plus MCF7 reporter cells; assays run by contract laboratories in Beijing, China and Istanbul, Turkey
• Exposure: Test compounds: K-975 (reference TEAD inhibitor), cisplatin (off-pathway cytotoxicity control), and computationally nominated candidates AG-690/36549045, AN-655/40856217, tiospirone and other library members including montelukast; 144-hour continuous exposure in the proliferation assays. No asbestos exposure was studied.
• Main results:
  • K-975 gave approximate IC50 values of about 45 nM in MSTO-211H and about 85 nM in NCI-H2052, with greater than 2,000 nM (reduced sensitivity) in NCI-H226
  • AG-690/36549045 and AN-655/40856217 showed no detectable antiproliferative activity (IC50 greater than 2,000 nM, the highest concentration tested) in all three mesothelioma lines
  • Cisplatin, tested at a single concentration of 100 µM, reduced viability to roughly 1 to 4 percent of vehicle across the three lines
  • In the exploratory MCF7 TEAD reporter, reductions in reporter signal for the nominated compounds co-occurred with loss of viability, with no compound suppressing reporter activity without viability loss
  • In the RealTime-Glo Annexin V assay in NCI-H226 cells, tiospirone produced no apoptosis induction while cisplatin did (early/progressive profile)
• The authors' conclusion: The authors concluded that the computationally nominated compounds did not reproduce the antiproliferative activity of the validated TEAD inhibitor, that apparent reporter activity was confounded by cytotoxicity, and that in silico nomination should be coupled to early functional and target-engagement assays
• Limitations the authors state:
  • No direct biochemical or cellular YAP–TEAD target-engagement assay was performed, so the authors cannot say whether the compounds bound TEAD
  • The TEAD reporter assay was exploratory, run in MCF7 cells rather than the mesothelioma models, without a TEAD-active reference compound, and confounded by cytotoxicity
  • The cell-line panel was limited to Hippo-altered mesothelioma
  • The authors state the findings may not generalize to other YAP/TAZ-dependent contexts
  • Only a few nominated compounds reached long-term proliferation testing, and solubility, permeability and intracellular exposure were not measured, so limited cellular uptake cannot be excluded
  • The study was descriptive, with qualitative consistency emphasized instead of formal statistical hypothesis testing

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Cisplatin, Discovery.

Related studies

• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)
• Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma — L. Evsen, P.J. Morris, et al. (2023)
• Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity — A. Gridnev, S. Maity, et al. (2022)
• Targeted degradation of specific TEAD paralogs by small molecule degraders — H. Chen, A. Gridnev, et al. (2024)
• Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma — Y. Sekido (2018)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)

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