Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers
Subhajit Maity1, Artem Gridnev1, Jyoti R Misra1
1Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
Abstract:
YAP/TAZ are transcriptional coactivators that function as the key downstream effectors of Hippo signaling. They are commonly misregulated in most human cancers, which exhibit a higher level of expression and nuclear localization of YAP/TAZ, and display addiction to YAP-dependent transcription. In the nucleus, these coactivators associate with TEA domain transcription factors (TEAD1-4) to regulate the expression of genes that promote cell proliferation and inhibit cell death. Together, this results in an excessive growth of the cancerous tissue. Further, YAP/TAZ play a critical role in tumor metastasis and chemotherapy resistance by promoting cancer stem cell fate. Furthermore, they affect tumor immunity by promoting the expression of PD-L1. Thus, YAP plays an important role in multiple aspects of cancer biology and thus, provides a critical target for cancer therapy. Here we discuss various assays that are used for conducting high-throughput screens of small molecule libraries for hit identification, and subsequent hit validation for successful discovery of potent inhibitors of YAP-transcriptional activity. Furthermore, we describe the advantages and limitations of these assays.
Insights
Dysregulated YAP/TAZ proteins drive cancer growth, metastasis, and resistance. This study reviews assays for discovering small molecule inhibitors targeting YAP-transcriptional activity for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ) are key Hippo signaling pathway effectors.
- YAP/TAZ are frequently overexpressed and hyperactivated in human cancers, promoting tumor growth and survival.
- These coactivators are crucial for cancer stem cell properties, metastasis, and chemotherapy resistance.
Purpose of the Study:
- To review and discuss assays for high-throughput screening (HTS) of small molecule libraries.
- To identify potent inhibitors of YAP/TAZ-transcriptional activity.
- To evaluate the advantages and limitations of various screening assays for YAP/TAZ inhibition.
Main Methods:
- High-throughput screening (HTS) assays for YAP/TAZ-transcriptional activity.
- Small molecule library screening for hit identification.
- Hit validation assays for inhibitor potency and specificity.
Main Results:
- YAP/TAZ nuclear localization and association with TEAD transcription factors drive oncogenic gene expression.
- YAP/TAZ promote cancer cell proliferation, inhibit apoptosis, and contribute to tumor metastasis.
- YAP/TAZ influence tumor immunity via PD-L1 expression and impact chemotherapy resistance.
Conclusions:
- YAP/TAZ are critical targets for novel cancer therapeutics.
- Effective assays are essential for discovering potent YAP/TAZ inhibitors.
- Targeting YAP/TAZ transcriptional activity holds promise for comprehensive cancer treatment strategies.
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