Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma

Mutations in the neurofibromatosis type 2 (NF2) gene, which impair or eliminate the expression of functional Merlin, are frequently observed in malignant mesothelioma. Merlin plays a critical role in activating the Hippo pathway, thereby preventing the nuclear translocation of YAP and TAZ—the pathway’s primary effectors. Once in the nucleus, YAP and TAZ associate with TEAD transcription factors to drive the expression of genes that promote cell proliferation and survival. In this study, we report the discovery of novel compounds that selectively inhibit YAP/TAZ-TEAD-mediated gene transcription by blocking TEAD auto-palmitoylation and disrupting GNE-7883 the YAP/TAZ-TEAD interaction. Through optimization, we developed potent analogs with excellent oral bioavailability and favorable pharmacokinetic properties. These compounds selectively inhibit the proliferation of NF2-deficient mesothelioma cells in vitro and suppress the growth of subcutaneous tumor xenografts in vivo. Our highly selective TEAD inhibitors offer a promising strategy to target the Hippo-YAP pathway, which has been notoriously challenging to drug and is frequently dysregulated in malignant mesothelioma and other YAP-driven cancers and diseases.