Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity

Our plain-English summary of Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity, by A. Gridnev, S. Maity, J.R. Misra (Frontiers in Oncology, 2022).

The study

• Authors: A. Gridnev, S. Maity, J.R. Misra
• Journal: Frontiers in Oncology
• Published: 2022;12:1021823
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2022 Gridnev, Maity and Misra.

In plain English

This was a laboratory drug-discovery study in cultured human cells. The authors carried out structure-based virtual ligand screening, docking a library of about 600,000 small molecules from PubChem against the crystal structure of TEAD2 (PDB ID 6UYC), and bought the top 50 compounds for testing in a HEK293 cell line carrying an 8XGTIIC firefly luciferase reporter of YAP/TAZ-TEAD activity. One compound, called JM7, inhibited the reporter with an IC50 of 972 nanomolar and did not inhibit firefly luciferase itself. JM7 reduced the YAP target gene transcripts CTGF and CYR61 in MDA-MB-231 breast, OVCAR-8 ovarian and NF2-mutant NCI-226 mesothelioma cells, without changing YAP or TEAD nuclear localization. It destabilized all four TEAD isoforms (reversed by the proteasome inhibitor MG132), modestly inhibited TEAD1 palmitoylation and significantly inhibited TEAD2-4 palmitoylation, and bound TEAD1-4 in cells in a thermal shift assay. Proliferation, colony formation and migration of the three cancer cell lines were reduced. The authors concluded JM7 is a novel lead compound.

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: laboratory study: computational (virtual ligand screening) drug discovery with cell-based biochemical and cell-biological experiments in human cancer cell lines
• Who was studied: Human cell lines only: HEK-293 (reporter and transfection assays), MDA-MB-231 breast cancer, OVCAR-8 ovarian cancer, and NCI-H226 (also written NCI-226) mesothelioma cells; no patients or animals
• Exposure: Treatment of cells with the newly identified small molecule JM7 (DMSO vehicle control; doses of 1, 2, 5 and 10 micromolar, plus logarithmic doses for IC50), in some experiments with alkyne palmitic acid or the proteasome inhibitor MG132
• Main results:
  • JM7 inhibited YAP transcriptional reporter (firefly luciferase) activity by 50% at 972 nanomolar in HEK293 cells carrying 8XGTIIC-Fluc with Rluc and YAP5SA
  • In MDA-MB-231 and OVCAR-8 cells, JM7 (1 or 2 micromolar) reduced CTGF and CYR61 transcripts dose-dependently; a similar dose-dependent decrease was seen in NF2-mutant NCI-226 mesothelioma cells
  • JM7 (2 micromolar) did not change the subcellular localization of YAP or TEAD in MDA-MB-231, OVCAR-8 or NCI-H226 cells
  • In HEK-293 cells expressing Myc-tagged TEAD1-4, JM7 (2 micromolar) modestly inhibited TEAD1 palmitoylation but significantly inhibited palmitoylation of TEAD2-4, and destabilized all four isoforms; MG132 (500 nM) reversed the destabilization
  • Cellular thermal shift assay indicated JM7 directly binds TEAD1-4 in cells, with more non-denatured Myc-TEAD at lower temperatures in JM7-treated samples
  • JM7 (2 micromolar) reduced proliferation (MTT) and migration (scratch assay) of MDA-MB-231 and OVCAR-8 cells; colony formation fell at 1, 2 and 5 micromolar in MDA-MB-231 and significantly at 5 micromolar in OVCAR-8; colony formation and wound healing were also attenuated in NCI-H226 cells
• The authors' conclusion: The authors concluded that JM7 is a novel-chemotype lead compound for developing more potent inhibitors of TEAD palmitoylation for cancer treatment
• Limitations the authors state:
  • The authors state that further structure-activity studies are needed to develop analogs that potently inhibit all four TEAD isoforms, since JM7 affected the isoforms unequally (effect on TEAD3 less drastic)
  • The authors state that in vivo efficacy was not assessed
  • The authors state that whether JM7 works in other NF2-mutant cancers remains to be examined
  • The authors offer an untested explanation for the weak measured effect on TEAD1 palmitoylation despite strong TEAD1 destabilization

Topics

Medical terms in this study, explained in our Lexicon: Discovery, Hippo Signaling Pathway, Carcinogenesis, Metastasis, Immunotherapy, Mesothelioma.

Related studies

• First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity — H. Liang, Y. Xu, et al. (2026)
• Targeted degradation of specific TEAD paralogs by small molecule degraders — H. Chen, A. Gridnev, 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)
• CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells — S. Jamal, V.T. Cheriyan, et al. (2014)
• Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity — L. Cao, J. Yang, et al. (2025)
• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models — G.J. Weiss, J.C. Loftus, et al. (2026)

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