Definition

An orally bioavailable inhibitor of the interaction between the transcription coactivator yes-associated protein 1 (YAP) and the transcription factor TEAD (TEA domain), with potential antineoplastic activity. Upon oral administration, YAP/TEAD inhibitor IAG933 disrupts the interaction between YAP and TEAD, thereby disrupting the interaction between the transcription coactivators YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and TEAD. This may inhibit YAP/TAZ-TEAD promoted gene transcription involved in tumor cell proliferation and survival. The Hippo-YAP/TAZ-TEAD pathway is dysregulated in certain cancers and diseases, including mesothelioma, neurofibromatosis type 2 (NF2)/large tumor suppressor 1 (LATS1)/ large tumor suppressor 2 (LATS2) mutated tumors and tumors with functional YAP/TAZ fusions. Mutations in the NF2 gene, common in malignant mesothelioma, limits the expression of Merlin, which is an activator of the Hippo pathway and suppresses the nuclear translocation of YAP and TAZ. LATS1/LATS2 are serine/threonine-protein kinases involved in the kinase cascade of the Hippo pathway; their activation leads to the inactivation of YAP/TAZ.