Recent studies have showed that IKBKE is overexpressed in several kinds of cancers and that IKBKE-knockdown inhibits tumor progression. In this article, we first verified that two glioblastoma cell lines, U87-MG and LN-229, were sensitive to CYT387 by measuring the half maximal inhibitory concentration (IC50) with a CCK-8 assay and then demonstrated that CYT387, as a potent IKBKE inhibitor, suppressed glioblastoma cell proliferation, migration and invasion. Additionally, CYT387 induced cell apoptosis and arrested the cell cycle at the G2/M checkpoint in vitro. Furthermore, we showed that CYT387 did not simply inhibit IKBKE activity but also decreased IKBKE expression at the protein level rather than at the mRNA level. We discovered that CYT387 restrained malignant tumor progression by activating the Hippo pathway in vitro. By coimmunoprecipitation (co-IP), we showed that IKBKE interacted with TEAD2 and YAP1, thus accelerating TEAD2 and YAP1 transport into the nucleus. In subsequent in vivo experiments, we found that CYT387 inhibited subcutaneous nude mouse tumor growth but had little impact on intracranial orthotopic xenografts, probably due to a limited ability to penetrate the blood–brain barrier (BBB). These results suggest that CYT387 has potential as a new antiglioblastoma drug, but an approach to allow passage through the blood–brain barrier (BBB) is needed.

中文翻译：

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CYT387 是一种有效的 IKBKE 抑制剂，通过激活 Hippo 通路抑制人类胶质母细胞瘤的进展

最近的研究表明 IKBKE 在几种癌症中过度表达，并且 IKBKE 敲低抑制了肿瘤进展。在本文中，我们首先通过使用 CCK-8 测定法测量半数抑制浓度 (IC50) 验证了两种胶质母细胞瘤细胞系 U87-MG 和 LN-229 对 CYT387 敏感，然后证明 CYT387 作为一种有效的IKBKE 抑制剂，抑制胶质母细胞瘤细胞增殖、迁移和侵袭。此外，CYT387 在体外诱导细胞凋亡并在 G2/M 检查点阻滞细胞周期。此外，我们发现 CYT387 不仅抑制 IKBKE 活性，而且还降低了蛋白质水平而非 mRNA 水平的 IKBKE 表达。我们发现 CYT387 通过在体外激活 Hippo 通路来抑制恶性肿瘤的进展。通过共免疫沉淀（co-IP），我们发现 IKBKE 与 TEAD2 和 YAP1 相互作用，从而加速了 TEAD2 和 YAP1 转运到细胞核中。在随后的体内实验中，我们发现 CYT387 抑制皮下裸鼠肿瘤生长，但对颅内原位异种移植物几乎没有影响，这可能是由于穿透血脑屏障 (BBB) 的能力有限。这些结果表明 CYT387 具有作为一种新的抗胶质母细胞瘤药物的潜力，但需要一种允许通过血脑屏障 (BBB) 的方法。可能是由于穿透血脑屏障 (BBB) 的能力有限。这些结果表明 CYT387 具有作为一种新的抗胶质母细胞瘤药物的潜力，但需要一种允许通过血脑屏障 (BBB) 的方法。可能是由于穿透血脑屏障 (BBB) 的能力有限。这些结果表明 CYT387 具有作为一种新的抗胶质母细胞瘤药物的潜力，但需要一种允许通过血脑屏障 (BBB) 的方法。