TEA domain transcription factor 1 (TEAD1) and TEA domain transcription factor 3 (TEAD3) (TEAD1/TEAD3)

TEA domain transcription factor 1 (TEAD1) and TEA domain transcription factor 3 (TEAD3) are members of the TEAD family of transcription factors, which serve as the primary nuclear effectors of the Hippo signaling pathway [2, 8]. These proteins regulate the expression of genes involved in cell proliferation, survival, and organ size control by interacting with co-activators such as YAP and TAZ [1, 10]. In many cancers, the Hippo pathway is dysregulated, leading to the hyperactivation of TEAD-mediated transcription and the promotion of tumor growth, metastasis, and drug resistance [2, 13]. TEAD1 and TEAD3 specifically have been shown to play redundant roles in maintaining epidermal proliferation and are overexpressed in various solid tumors, including mesothelioma and squamous cell carcinomas [3, 17]. Therapeutic strategies targeting these proteins focus on inhibiting their palmitoylation—a post-translational modification required for their stability and activity—or disrupting their interaction with YAP/TAZ [2, 5]. Several small-molecule inhibitors, such as K-975 and IK-930, are currently in development to target the TEAD-YAP/TAZ axis in oncology [2]. While TEAD inhibitors show significant promise in treating NF2-deficient and other Hippo-driven malignancies, clinical development must carefully manage potential safety concerns such as nephrotoxicity [5, 12]. Additionally, their roles in embryonic development, particularly in heart and placental formation, suggest potential for developmental toxicity if targeted systemically [4, 10]. Monitoring biomarkers like NF2 status and CTGF expression is crucial for patient selection and assessing therapeutic efficacy [2, 10].

Other names

Transcriptional enhancer factor TEF-1Transcriptional enhancer factor TEF-5DTEF-1ETFR-1TCF13TEAD5NTEF-1TEA domain family member 1TEA domain family member 3

Inhibition of TEAD palmitoylation via covalent binding to the central hydrophobic pocket and disruption of the protein-protein interaction between TEAD and its co-activators YAP/TAZ.