Targeting the Hippo Pathway: Development and Efficacy of a Novel TEAD Inhibitor in Malignant Pleural Mesothelioma

The objective of this study was to investigate the role of the Hippo signaling pathway in organ development and its connection to various cancers. YAP or TAZ, acting as transcriptional co-activators, form a complex with TEAD, which is activated when upstream Hippo pathway factors are inactivated due to genetic alterations. This activation leads to increased cell proliferation and drug resistance. The study focused on malignant pleural mesothelioma (MPM), a cancer with genetic alterations in Hippo pathway genes, and the development of a TEAD inhibitor, K-975, to counteract these effects.

The inhibitory activity of K-975 on the YAP/TAZ-TEAD protein-protein interaction was assessed using surface plasmon resonance and co-immunoprecipitation assays. Additionally, the effect of K-975 on the palmitoylation status of TEAD was evaluated. The three-dimensional structure of the YAP-binding domain of TEAD1 in complex with K-975 was determined through X-ray crystallography. The anti-tumor effect of K-975 was tested on MPM cell lines, and toxicity studies were conducted in rats and monkeys using a derivative of K-975.

Results showed that K-975 effectively inhibited the YAP-TEAD and TAZ-TEAD interactions in human MPM cells and suppressed the palmitoylation of TEAD. The crystal structure indicated that K-975 binds directly to a conserved cysteine residue in the YAP-binding domain of TEAD1, a known site for S-palmitoylation. K-975 also demonstrated a strong inhibitory effect on cell proliferation and induced gene expression changes similar to YAP knockdown. In vivo experiments revealed that K-975 significantly reduced tumor growth and improved survival in xenograft models. However, the toxicity studies suggested potential renal toxicity with a K-975 derivative.

In conclusion, the study synthesized a novel drug, K-975, which directly binds to TEAD protein and inhibits the YAP/TAZ-TEAD interaction. K-975 displayed a potent anti-tumor effect in pre-clinical MPM models. Despite concerns regarding renal toxicity, the potential for a K-975 derivative as an effective drug candidate for MPM therapy is promising.