Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity
Artem Gridnev1, Subhajit Maity1, Jyoti R Misra1
1Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, United States.
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.
Insights
A new molecule, JM7, inhibits YAP/TAZ oncogenic activity by targeting TEAD proteins. This discovery offers a novel therapeutic strategy for cancers driven by the Hippo pathway, impacting cell growth and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The Hippo signaling pathway's coactivators, YAP and TAZ, are crucial for cell growth and are deregulated in many cancers.
- Their disordered structure makes direct targeting difficult, necessitating alternative therapeutic strategies.
- YAP/TAZ function by interacting with TEAD transcription factors, making TEADs a potential indirect target.
Purpose of the Study:
- To discover and characterize a novel small molecule inhibitor of YAP activity.
- To investigate the mechanism of action for inhibiting YAP/TAZ oncogenic functions.
- To evaluate the therapeutic potential of the identified inhibitor in cancer models.
Main Methods:
- Structure-based virtual ligand screening.
- Biochemical and cell biological assays to assess inhibitor activity.
- Cellular thermal shift assay to confirm direct binding to TEAD proteins.
Main Results:
- Identified JM7, a small molecule inhibitor of YAP transcriptional reporter activity (IC50 = 972 nM).
- JM7 inhibits YAP target gene expression by preventing TEAD autopalmitoylation, leading to TEAD instability.
- JM7 directly binds to TEAD1-4 in cancer cells and impairs proliferation, colony formation, and migration in mesothelioma, breast, and ovarian cancer cell lines.
Conclusions:
- JM7 is a novel lead compound targeting TEAD palmitoylation.
- This approach offers a new strategy for inhibiting YAP/TAZ oncogenic activity in cancer.
- Further development of JM7 could lead to potent therapeutics for YAP-driven cancers.
