Repurposing of Drugs Targeting YAP-TEAD Functions

Abstract

Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds.

A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations

“…Thus, YAP/TAZ would be a promising drug target for metastatic cancer. Although no effective clinical drugs targeting YAP/TAZ are available, multiple direct and indirect inhibitors for YAP/TAZ have been developed (178). Verteporfin, which is a photosensitizer for photodynamic therapy, has been known to inhibit YAP/TAZ activity by blocking YAP/TAZ-TEAD interaction and downregulating YAP/TAZ expression (179,180).…”

“…These inhibitors may have better therapeutic effects with less toxicity than verteporfin because of their specificity. As an alternative approach, YAP/TAZ upstream regulators, in particular protein kinases and other enzymes, would serve as potential drug targets for attenuating YAP/TAZ activity (178). However, YAP/TAZ is regulated by many upstream regulators and the regulatory mechanism may be dependent on cell context.…”

Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy

“…Once activated, LATS1/2 further promote the signalling cascade by phosphorylating YAP at Ser127. Phosphorylated YAP is degraded in the cytoplasm, while dephosphorylated YAP can enter the nucleus and bind to TEAD1–4 to initiate transcription of downstream target genes, thereby exerting proliferation and anti-apoptosis effects 34 . YAP signalling is involved in the pathogenesis of cystic nephropathy and is up-regulated in fibroblasts to increase the synthesis of the extracellular matrix and to promote renal fibrosis 35 .…”

Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?

“…Considering the Hippo signaling pathway's critical role in many pathologies, targeting that pathway seems to be an interesting therapeutic approach, particularly in oncology (Figure 4). Most inhibitors focus on the inhibition of YAP-TEAD interaction, but other compounds that inhibit YAP upstream regulators have been tested [104]. The most used compound is verteporfin, a benzoporphyrin-derived molecule already in clinical use in the treatment of age-related macular degeneration through photodynamic therapy.…”