Yes-associated protein–TEA domain transcription factor interaction inhibitor (YAP–TEAD interaction inhibitor)

The YAP–TEAD interaction inhibitor targets the direct binding between yes-associated protein (YAP), a transcriptional coactivator, and TEA domain (TEAD) family transcription factors. This interaction is central to YAP’s role in regulating gene expression downstream of the Hippo pathway, which controls cell growth, proliferation, and survival. Aberrant activation of YAP–TEAD signaling is implicated in the development and progression of multiple cancers. Small molecules such as IAG933, NSC682769, and CPD3/CPD3.1, as well as allosteric TEAD inhibitors (such as GNE-7883), have been developed to specifically block this protein–protein interaction. Disruption of YAP–TEAD leads to reduced oncogenic gene expression and induces apoptosis in cancer cells, with preclinical studies showing promising effects across various tumor models driven by Hippo pathway alteration. Emerging data suggest multiple mechanisms for these inhibitors, including direct competition, allosteric changes to TEAD, and cofactor switching. While these compounds hold significant therapeutic promise, challenges remain regarding specificity, potential resistance, and impacts on normal tissue homeostasis[1][2][3][4][5][6][7][8].

Other names

YAP/TEAD interaction inhibitorYAP–TEAD inhibitorYAP–TEAD interface inhibitorTEAD inhibitorHippo pathway inhibitor

Direct disruption of the YAP–TEAD protein–protein interaction, blocking transcriptional activation of YAP/TEAD target genes and inhibiting YAP-driven oncogenic processes. Allosteric modulation of TEAD to prevent YAP/TAZ binding by altering the lipid pocket. Induction of cofactor switch (enhanced VGLL4–TEAD interaction), repressing YAP signaling.