Transcriptional enhancer factor TEAD and Yes-associated protein 1 complex (TEAD-YAP1)

The Transcriptional enhancer factor TEAD and Yes-associated protein 1 (TEAD-YAP1) complex is the primary transcriptional effector of the Hippo signaling pathway, which plays a critical role in regulating organ size, cell proliferation, and tissue homeostasis [PMID: 29109595]. YAP1 serves as a transcriptional co-activator that lacks its own DNA-binding domain and must physically associate with TEAD family transcription factors (TEAD1-4) to initiate the transcription of genes involved in cell survival and the epithelial-mesenchymal transition [PMID: 18568018]. In many human cancers, the Hippo pathway is disrupted by mutations in upstream tumor suppressors such as NF2 or LATS1/2, leading to the constitutive activation and nuclear localization of YAP1 [PMID: 25298330]. This hyperactivation drives tumor growth, metastasis, and resistance to conventional therapies, making the TEAD-YAP1 interaction a high-value target for drug development. Current therapeutic strategies involve small molecules that disrupt this protein-protein interaction, either by binding to a conserved hydrophobic palmitoylation pocket within the TEAD protein or by directly blocking the YAP1-binding interface [PMID: 33031744]. Clinical candidates like VT3989 and IK-930 are currently being investigated for the treatment of NF2-deficient mesothelioma and other Hippo-pathway-altered solid tumors [ClinicalTrials.gov NCT04665206]. However, drug development faces challenges regarding potential toxicities, particularly in the kidney and during wound healing, where the Hippo pathway maintains physiological function.

Other names

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

Small molecule inhibition of the protein-protein interaction between TEAD transcription factors and the YAP1 co-activator, typically by binding to the conserved TEAD palmitoylation pocket to allosterically disrupt binding or by directly blocking the YAP-binding interface.