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Identification of YAP regulators through high-throughput screening and NanoBiT-based validation-drug repositioning
Ji-Youn Lim1, Eui-Hwan Choi1, Yujeong Kim2
1New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
Abstract:
Yes-associated protein (YAP), a key co-transcription factor of the Hippo pathway, is a promising drug target for cancer therapy due to its critical role in promoting cell proliferation, survival, and tumor progression when dysregulated. While most Hippo pathway-targeting drugs focus on disrupting TEAD-YAP interactions or modulating the MST or LATS kinase cascade, new approaches are needed to identify small molecules that regulate YAP activity. In this study, we conducted high-throughput screening of FDA-approved drugs to discover potential YAP modulators. Using a NanoBiT-based system, which enables real-time and quantitative measurement of protein interactions, combined with phenotype-based assays in EGFP-YAP-expressing cells, we identified compounds that activate or inhibit YAP function. Among the identified YAP regulators, the microtubule destabilizer vinorelbine promoted YAP nuclear localization and transcriptional activation, while the antipsychotic drug thioridazine enhanced YAP phosphorylation at Ser127, resulting in its cytoplasmic retention and reduced transcriptional activity, effectively suppressing cancer cell growth. These findings demonstrate the potential of FDA-approved drugs in modulating YAP activity and present a novel screening strategy for developing YAP-targeting therapeutics. Furthermore, this approach can be extended to identify modulators of other signaling pathways, advancing drug discovery for a wide range of diseases.
Insights
Researchers screened FDA-approved drugs to find new ways to control Yes-associated protein (YAP) in cancer. They found vinorelbine activates YAP, while thioridazine inhibits it, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Yes-associated protein (YAP) is crucial for cancer cell growth and survival when its regulation is disrupted.
- Current therapies targeting the Hippo pathway often focus on TEAD-YAP interactions or kinase cascades.
- Novel strategies are needed to identify small molecules that effectively modulate YAP activity.
Purpose of the Study:
- To screen FDA-approved drugs for novel YAP modulators.
- To establish a new screening method for YAP-targeting therapeutics.
- To explore repurposing existing drugs for cancer therapy by targeting YAP.
Main Methods:
- High-throughput screening of FDA-approved drug libraries.
- Utilized a NanoBiT-based system for real-time protein interaction analysis.
- Employed phenotype-based assays in EGFP-YAP-expressing cells to assess YAP function.
Main Results:
- Identified vinorelbine as an activator of YAP, promoting nuclear localization and transcriptional activity.
- Discovered thioridazine as an inhibitor of YAP, inducing Ser127 phosphorylation and cytoplasmic retention.
- Demonstrated that thioridazine effectively suppresses cancer cell growth by inhibiting YAP.
Conclusions:
- FDA-approved drugs can be repurposed to modulate YAP activity, offering a faster route to cancer therapeutics.
- The developed screening strategy is effective for identifying YAP modulators and can be adapted for other signaling pathways.
- This approach holds promise for advancing drug discovery for various diseases by targeting key signaling molecules like YAP.
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