Kaneda Ayumi, Seike Toshihiro, Danjo Tomohiro, Nakajima Takahiro, Otsubo Nobumasa, Yamaguchi Daisuke, Tsuji Yoshiro, Hamaguchi Kaori, Yasunaga Mai, Nishiya Yoichi, Suzuki Michihiko, Saito Jun-Ichi, Yatsunami Rie, Nakamura Satoshi, Sekido Yoshitaka, Mori Kiyotoshi
R&D Division, Kyowa Kirin Co., Ltd Shizuoka, Japan.
School of Life Science and Technology, Tokyo Institute of Technology Yokohama, Japan.
Am J Cancer Res. 2020 Dec 1;10(12):4399-4415. eCollection 2020.
The Hippo signaling pathway regulates cell fate and organ development. In the Hippo pathway, transcriptional enhanced associate domain (TEAD) which is a transcription factor is activated by forming a complex with yes-associated protein 1 (YAP1) or transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1). Hyper-activation of YAP1/TAZ, leading to the activation of TEAD, has been reported in many cancers, including malignant pleural mesothelioma (MPM). Therefore, the YAP1/TAZ-TEAD complex is considered a novel therapeutic target for cancer treatment. However, few reports have described YAP1/TAZ-TEAD inhibitors, and their efficacy and selectivity are poor. In this study, we performed a high-throughput screening of a neurofibromin 2 (NF2)-deficient MPM cell line and a large tumor suppressor kinase 1/2 (LATS1/2)-deficient non-small-cell lung cancer cell line using a transcriptional reporter assay. After screening and optimization, K-975 was successfully identified as a potent inhibitor of YAP1/TAZ-TEAD signaling. X-ray crystallography revealed that K-975 was covalently bound to an internal cysteine residue located in the palmitate-binding pocket of TEAD. K-975 had a strong inhibitory effect against protein-protein interactions between YAP1/TAZ and TEAD in cell-free and cell-based assays. Furthermore, K-975 potently inhibited the proliferation of NF2-non-expressing MPM cell lines compared with NF2-expressing MPM cell lines. K-975 also suppressed tumor growth and provided significant survival benefit in MPM xenograft models. These findings indicate that K-975 is a strong and selective TEAD inhibitor with the potential to become an effective drug candidate for MPM therapy.
河马信号通路调节细胞命运和器官发育。在河马通路中，作为转录因子的转录增强子结合结构域（TEAD）通过与Yes相关蛋白1（YAP1）或含PDZ结合基序的转录共激活因子（TAZ，也称为WWTR1）形成复合物而被激活。YAP1/TAZ的过度激活导致TEAD的激活，这在包括恶性胸膜间皮瘤（MPM）在内的许多癌症中都有报道。因此，YAP1/TAZ-TEAD复合物被认为是癌症治疗的一个新的治疗靶点。然而，很少有报道描述YAP1/TAZ-TEAD抑制剂，并且它们的疗效和选择性都很差。在本研究中，我们使用转录报告分析对神经纤维瘤蛋白2（NF2）缺陷的MPM细胞系和大肿瘤抑制激酶1/2（LATS1/2）缺陷的非小细胞肺癌细胞系进行了高通量筛选。经过筛选和优化，K-975成功地被鉴定为YAP1/TAZ-TEAD信号的有效抑制剂。X射线晶体学显示，K-975与位于TEAD棕榈酸结合口袋中的一个内部半胱氨酸残基共价结合。在无细胞和基于细胞的分析中，K-975对YAP1/TAZ和TEAD之间的蛋白质-蛋白质相互作用有很强的抑制作用。此外，与表达NF2的MPM细胞系相比，K-975能有效抑制不表达NF2的MPM细胞系的增殖。K-975还能抑制MPM异种移植模型中的肿瘤生长并提供显著的生存益处。这些发现表明，K-975是一种强效且选择性的TEAD抑制剂，有潜力成为MPM治疗的有效候选药物。
