The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma.
The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma.
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发表时间：
2020
影响因子：
5.3
通讯作者：
Ayumi Kaneda;Toshihiro Seike;Tomohiro Danjo;T. Nakajima;N. Otsubo;Daisuke Yamaguchi;Y. Tsuji;Kaori Hamaguchi;M. Yasunaga;Y. Nishiya;Michihiko Suzuki;J. Saito;R. Yatsunami;Satoshi Nakamura;Y. Sekido;Kiyotoshi Mori
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作者：
Ayumi Kaneda;Toshihiro Seike;Tomohiro Danjo;T. Nakajima;N. Otsubo;Daisuke Yamaguchi;Y. Tsuji;Kaori Hamaguchi;M. Yasunaga;Y. Nishiya;Michihiko Suzuki;J. Saito;R. Yatsunami;Satoshi Nakamura;Y. Sekido;Kiyotoshi Mori
Hippo信号通路调节细胞命运和器官发育。在Hippo通路中，转录增强相关结构域（TEAD）是一种转录因子，通过与yes相关蛋白1（YAP 1）或转录辅激活因子与PDZ结合基序（TAZ，也称为WWTR 1）形成复合物而被激活。在许多癌症中，包括恶性胸膜间皮瘤（MPM），已经报道了YAP 1/TAZ的过度活化，导致TEAD的活化。因此，YAP 1/TAZ-TEAD复合物被认为是癌症治疗的新靶点。然而，很少有报道描述YAP 1/TAZ-TEAD抑制剂，并且它们的效力和选择性差。在这项研究中，我们进行了高通量筛选的神经纤维蛋白2（NF 2）缺陷的MPM细胞系和大肿瘤抑制激酶1/2（LATS 1/2）缺陷的非小细胞肺癌细胞系使用转录报告基因分析。经过筛选和优化，K-975被成功鉴定为YAP 1/TAZ-TEAD信号转导的有效抑制剂。X射线晶体学显示，K-975与位于TEAD棕榈酸结合口袋中的内部半胱氨酸残基共价结合。在无细胞和基于细胞的试验中，K-975对YAP 1/TAZ和TEAD之间的蛋白质-蛋白质相互作用具有强抑制作用。此外，与表达NF 2的MPM细胞系相比，K-975可有效抑制NF 2非表达MPM细胞系的增殖。K-975还可抑制肿瘤生长，并在MPM异种移植模型中提供显著的生存获益。这些结果表明，K-975是一种强效的选择性TEAD抑制剂，有可能成为MPM治疗的有效候选药物。
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.