Yes-associated protein 1 (YAP1) - Transcriptional enhancer factor domain (TEAD) protein-protein interaction (YAP-TEAD PPI)

The Yes-associated protein 1 (YAP1) - Transcriptional enhancer factor domain (TEAD) protein-protein interaction is the central terminal component of the Hippo signaling pathway, which plays a fundamental role in controlling organ size, cell proliferation, and tissue homeostasis (Nature Reviews Drug Discovery, 2019). YAP1 and its paralog TAZ function as transcriptional co-activators that lack intrinsic DNA-binding activity and must interact with TEAD family transcription factors (TEAD1-4) to regulate the expression of genes that promote cell survival and epithelial-to-mesenchymal transition (UniProt, P46937). In many human cancers, particularly those harboring mutations in Neurofibromin 2 (NF2) or Large Tumor Suppressor Kinases (LATS1/2), the Hippo pathway is inactivated, leading to the constitutive nuclear localization of YAP1 and hyperactivation of TEAD-mediated transcription (PubMed, 30447548). Therapeutic strategies targeting this interaction include small molecules that bind to the highly conserved palmitoylation pocket of TEAD or directly block the YAP-TEAD binding interface (Journal of Medicinal Chemistry, 2022). Several inhibitors, such as VT3989 and IK-930, are currently in clinical development for the treatment of malignant pleural mesothelioma and other Hippo-pathway-deficient solid tumors (ClinicalTrials.gov, NCT04665206).

Other names

YAP1-TEAD interactionTAZ-TEAD interactionHippo pathway effector complexYAP-TEAD complex

Inhibition of the protein-protein interaction between the transcriptional co-activators YAP1 or TAZ and the TEAD family of transcription factors, primarily through small-molecule binding to the TEAD palmitoylation pocket or the YAP-binding interface, which prevents the formation of a functional transcriptional complex (Nature Reviews Drug Discovery, 2019; Journal of Medicinal Chemistry, 2022).