Abstract
Simple SummaryCancer is a disease in which cells grow in an uncontrolled manner. This can be due to excessive cell proliferation or reduced cell death or a combination of the two. The Hippo signaling pathway, when misregulated, promotes excessive growth and cancer development by inducing uncontrolled cell proliferation and inhibiting cell death. This is achieved due to unregulated activity of the oncogenic effector of this pathway, YAP/TAZ. Therefore, it is critical to develop inhibitors to disrupt YAP activity in cancers. This article reviews the different types of assays that are used in development of small molecule inhibitors for YAP activity in cancers.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.
Highlights
The Hippo signaling pathway plays a central role in regulation of cell proliferation, cell death and cell fate determination
Hypo/unphosphorylated YAP/TAZ translocate into the nucleus and associate with TEAD1-4 transcription factors to regulate the expression of a large number of target genes [2,3]
The Hippo pathway effectors, YAP/TAZ are commonly misregulated in most human cancers and play a critical role in tumor growth, metastasis, immunity, and therapy resistance
Summary
The Hippo signaling pathway plays a central role in regulation of cell proliferation, cell death and cell fate determination. Mutations in several of the residues cancer, are involved in fibrosis, where they play an important role in the in this region completely disrupt YAP–TEAD interaction This interface is very conversion of fibroblasts into contractile myofibroblasts, which secrete excessive amounts of collagen and other connective tissue components. Structural studies revealed that YAP binds to TEAD tightly by engaging the N-terminal 100 amino acids, and this interaction is mediated by three interfaces (Figure 1B) [14–18]. Cancers 2022, 14, 1029 current efforts are directed toward the development of molecules that destabilize TEAD and allosterically inhibit its interaction with YAP. Since the central hydrophobic pocket is the most druggable site, currently, significant effort is aimed at developing potent inhibitors that bind to this site This site is highly conserved among the four TEAD isoforms. We describe different assays that are used for the successful screening of small molecule libraries for the identification and subsequent validation of YAP activity inhibitors
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