DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC). Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. In this report, we show that DHX9 knockdown increased RNA/DNA secondary structures and replication stress, resulting in cell cycle arrest and the onset of apoptosis in cancer cells with MSI-H/dMMR. ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity. Chemical inhibition of DHX9 enzymatic activity elicited similar selective effects on cell proliferation as seen with genetic knockdown. In addition, ATX968 induced robust and durable responses in an MSI-H/dMMR xenograft model but not in a microsatellite stable (MSS)/proficient mismatch repair (pMMR) model. These preclinical data validate DHX9 as a target for the treatment of patients with MSI-H/dMMR. Additionally, this potent and selective inhibitor of DHX9 provides a valuable tool with which to further explore the effects of inhibition of DHX9 enzymatic activity on the proliferation of cancer cells in vitro and in vivo.

中文翻译：

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DHX9 的强效选择性小分子抑制剂可消除错配修复缺陷的微卫星不稳定癌症的增殖


DHX9 是一种多功能 DExH-box RNA 解旋酶，在转录、翻译和维持基因组稳定性方面具有重要作用。DHX9 表达升高在多种癌症类型中很明显，包括结直肠癌 （CRC）。具有错配修复缺陷 （dMMR） 的微卫星不稳定高 （MSI-H） 肿瘤对 DHX9 表现出很强的依赖性，使该解旋酶成为肿瘤药物发现的有吸引力的靶标。在本报告中，我们表明 DHX9 敲低增加了 RNA/DNA 二级结构和复制应激，导致 MSI-H/dMMR 癌细胞周期停滞和细胞凋亡。ATX968 被鉴定为 DHX9 解旋酶活性的有效选择性抑制剂。DHX9 酶活性的化学抑制对细胞增殖的选择性影响与基因敲低相似。此外，ATX968 在 MSI-H/dMMR 异种移植模型中诱导了稳健和持久的反应，但在微卫星稳定 （MSS）/熟练错配修复 （pMMR） 模型中没有诱导。这些临床前数据验证了 DHX9 是治疗 MSI-H/dMMR 患者的靶点。此外，这种有效的选择性 DHX9 抑制剂提供了一种有价值的工具，可用于进一步探索抑制 DHX9 酶活性对体外和体内癌细胞增殖的影响。