VT104

The Hippo pathway governs organ size and tissue homeostasis, regulating several fundamental cellular processes such as cell proliferation, migration, apoptosis and cell-fate decision. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its main two-terminal effectors, mediating most of its physiological functions. When the Hippo upstream pathway inhibition promotes YAP/TAZ translocation to the nucleus, where they form the active complex with the transcriptional-enhancer-associate-domain (TEAD) family of transcription factors to control the expression of target genes. YAP and TAZ activity is key in the amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and cell proliferation. In tumours, they play an important role in cancer development, progression and metastasis. As such, they are attractive targets for cancer therapy and for regenerative medicine applications. In particular, regulating the complex formation/interactions of YAP/TAZ with TEAD, and subsequent target gene activation has been reported as a valuable strategy. The small-molecule VT104 is a potent and selective TEAD inhibitor that blocks TEAD auto-palmitoylation, and thus disrupt the interaction with YAP/TAZ. In particular, this is a pan-TEAD palmitoylation inhibitor, that inhibits all four TEAD 1-4 proteins by binding directly to TEAD in the central lipid pocket. VIT104 shows strong antitumor efficacy in the human mesothelioma NCI-H226 CDX model. The compound has been identified through a comprehensive set of cellular, biochemical, biophysical and structural studies and in vivo investigation.