Illuminating Clinical TEAD Inhibitors Through Structural Biology

T he Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating organ size, tissue regeneration, and homeostasis by coordinating cell proliferation, differentiation, and apoptosis.Functionally, it acts as a tumor suppressor pathway by restraining the activity of two key oncogenic transcriptional coactivators, Yesassociated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). 1 Under normal physiological conditions, activation of the Hippo pathway leads to prevention of YAP/TAZ from driving gene expression.In many cancers, however, the Hippo pathway is dysregulated, resulting in the nuclear accumulation of YAP/TAZ, aberrant cell proliferation and tumor progression.Thus, disrupting YAP-TEAD interaction represents a promising approach for cancer treatment.2 The human TEAD proteins contain a conserved N-terminal DNA-binding domain and a C-terminal YAP-binding domain (YBD) which is responsible for binding to YAP/TAZ.Although TEAD1-4 exhibit distinct expression patterns across different tissues, they share highly conserved structural features.Considerable efforts have been devoted to developing both pan-TEAD inhibitors and isoform-specific inhibitors through disrupting YAP/TAZ-TEAD interactions.Structural biology of TEAD proteins and their interactions with YAP/ TAZ provided important information for drug discovery.First, the structural basis to understand TEAD-YAP interactions indicates the potential challenges due to the lack of a druggable pocket at the interface between the protein-potein interaction.Second, structures of TEAD proteins reveal the palmitoylation pocket, providing a basis for uncovering the novel function of TEAD.Lastly, structure-based drug design accelerates the rational design of TEAD modulators.In this editorial, we discuss the roles of structural biology in developing clinical inhibitors (Table 1) to modulate YAP-TEAD interactions and provide an outlook for future strategies to drug TEAD.X-ray crystallographic studies showed that the YAP-binding domain of TEAD adopts an immunoglobulin-like β-sandwich fold composed of 12 β-strands and four α-helices.The TEADbinding region of free YAP is largely unstructured but adopts defined secondary structures upon binding to TEAD.The TEAD-binding domain of YAP forms three key structural elements namely a β-strand, an α-helix, and an Ω-loop through three binding interfaces on TEAD (Figure 1A).Cooperative interactions between these structural elements further enhance the overall binding affinity of YAP for TEAD, suggesting the challenges in developing inhibitors to disrupt protein interactions through targeting individual binding site.3 Despite the challenge, disrupting the TEAD-YAP interaction has emerged as a promising strategy to modulate TEAD function.