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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides
Zheng Zhou1, Taishan Hu2, Zhiheng Xu2
1*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China joe.zhou.jz2@roche.com.
Abstract:
Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) association is essential for YAP-driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP-like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP-TEAD interaction in vitro. To confirm that blocking YAP-TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant-negative mutation (Y406H) of TEAD1 to abolish YAP-TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP-induced oncogenesis.
Insights
Targeting the Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) interaction shows promise for cancer therapy. Engineered peptides disrupt YAP-TEAD binding, reducing tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The Hippo signaling pathway regulates organ size and is implicated in tumorigenesis.
- The interaction between Yes-associated protein (YAP) and transcriptional enhancer activation domain family member (TEAD) is crucial for YAP-driven oncogenic activity.
- TEAD is essential for YAP-mediated oncogenesis but dispensable for normal tissue growth.
Purpose of the Study:
- To design YAP-like peptides targeting the YAP-TEAD interface.
- To validate TEAD as a therapeutic target for blocking YAP-driven oncogenesis.
Main Methods:
- Design and engineering of YAP-mimicking peptides (17mer) to bind TEAD.
- Crystallographic analysis to confirm disulfide bond formation in engineered peptides.
- In vitro assays to assess the disruption of YAP-TEAD interaction.
- In vivo studies using a hepatocellular carcinoma xenograft model with a dominant-negative TEAD1 mutation.
Main Results:
- Engineered YAP-like peptides demonstrated enhanced potency in disrupting YAP-TEAD interaction in vitro.
- Crystallography confirmed the induced disulfide formation in engineered peptides.
- A dominant-negative TEAD1 mutation significantly reduced tumor growth rate in a hepatocellular carcinoma xenograft model, validating TEAD as a target.
Conclusions:
- Targeting the YAP-TEAD interaction interface on TEAD is a viable therapeutic strategy.
- Engineered peptides offer a potential approach to inhibit YAP-TEAD-driven oncogenesis.
- Inhibiting TEAD presents a promising avenue for anticancer therapies, particularly for YAP-driven cancers.
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