Hippo signaling pathway is known to regulate organ size and tissue homeostasis. In Hippo signaling pathway, YAP/TAZ works as a transcriptional co-activator and forms a transcriptional complex with TEAD. When the upstream factors are inactivated, TEAD is activated and forms a complex with YAP/TAZ resulting in enhancement of cell proliferation, migration, survival etc. Malignant pleural mesothelioma (MPM) is one of cancer types which has genetic alterations in Hippo pathway genes. Therefore, YAP/TAZ-TEAD inhibitor has the potential to be a new drug for the treatment of MPM.<br/><br/>K-975 was identified from our high throughput screening campaign with CTGF-luciferase reporter assay system and subsequent structure optimization. K-975 indicated a highly potent inhibitory effect of cell proliferation against NCI-H226 (a human MPM cell line). <i>In vivo</i> experiments, orally administrated K-975 strongly suppressed the tumor growth in several s.c. xenograft mouse models and showed a significant survival benefit in an orthotopic xenograft mouse model. We also identified that TEAD was the target protein of K-975 and proved that K-975 directly bound to a cysteine residue in YAP-binding domain of TEAD1 determined by X-ray crystallography. This presentation will focus on the discovery of a novel TEAD inhibitor, as well as identification of its mechanism of action.

Discovery of a novel TEAD inhibitor for the treatment of malignant pleural mesothelioma

ACS Spring Meeting 2021

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