Yes-associated protein 1–TEA domain family member (YAP1–TEAD) protein-protein interface (YAP1–TEAD PPI)

The Yes-associated protein 1–TEA domain family member (YAP1–TEAD) protein-protein interface is the terminal effector of the Hippo signaling pathway, which governs organ size, tissue regeneration, and stem cell self-renewal (Panciera et al., 2017, Nature Reviews Molecular Cell Biology). YAP1 serves as a transcriptional co-activator that lacks DNA-binding activity and must physically associate with TEAD transcription factors (TEAD1-4) to drive the expression of pro-proliferative and anti-apoptotic genes like CTGF and CYR61 (Pobbati & Hong, 2020, Cells). Dysregulation of this interface, often through loss-of-function mutations in upstream regulators like NF2 or LATS1/2, leads to hyperactivation of YAP1 and is a hallmark of various malignancies, including mesothelioma and uveal melanoma (Harvey et al., 2013, Nature Reviews Cancer). Pharmacological targeting of this interface primarily involves small molecules that bind to a conserved hydrophobic palmitoylation pocket on TEAD, which allosterically or orthosterically disrupts YAP1 binding (Noland et al., 2016, Structure). Several inhibitors, such as IK-930 and VT-104, are currently in clinical trials for Hippo-pathway-deficient solid tumors (ClinicalTrials.gov, 2024). However, therapeutic challenges include potential toxicity in the kidney and liver, where Hippo signaling is required for normal physiological maintenance (Dey et al., 2020, Nature Communications). The development of these inhibitors represents a significant shift toward targeting "undruggable" transcription factor complexes in precision oncology.

Other names

YAP-TEAD complexYAP1-TEAD interactionHippo pathway effector complexYAP/TAZ-TEAD interfaceYAP1/TEAD transcriptional complex

Small molecule inhibition of the protein-protein interaction between YAP1 and TEAD transcription factors, often achieved by binding to the conserved TEAD palmitoylation pocket to allosterically disrupt YAP1 binding or by directly blocking the YAP-binding surface to prevent transcriptional activation of Hippo pathway target genes (Pobbati & Hong, 2020, Cells).