Sekine Saaya, Takase Shohei, Hayase Runa, Noritsugu Kota, Maemoto Yuki, Ichikawa Yasue, Ogawa Kenji, Kondoh Yasumitsu, Osada Hiroyuki, Yoshida Minoru, Ito Akihiro
Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
Biosci Biotechnol Biochem. 2023 Apr 24;87(5):501-510. doi: 10.1093/bbb/zbad022.
TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.
TEAD是一种转录因子，负责肿瘤抑制因子Hippo信号通路的输出。TEAD的转录活性需要与其转录共激活因子YAP进行分子相互作用。TEAD的异常激活与肿瘤发生密切相关，并与不良预后相关，这表明靶向YAP-TEAD系统的抑制剂有望成为抗肿瘤药物。在本研究中，我们鉴定出天然产物生物碱吐根碱的类似物NPD689是YAP-TEAD相互作用的抑制剂。NPD689抑制了TEAD的转录活性，并降低了人恶性胸膜间皮瘤和非小细胞肺癌细胞的活力，但不影响正常人胸膜间皮细胞的活力。我们的结果表明，NPD689不仅是阐明YAP-TEAD系统生物学作用的一种新的有用化学工具，而且还具有作为开发靶向YAP-TEAD相互作用的癌症治疗药物的起始化合物的潜力。
