The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1 in vitro and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.

中文翻译：

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用于 B 细胞癌治疗的肿瘤靶向 IRE-1 抑制剂的开发

IRE-1 激酶/RNase 剪接 XBP-1 基因的 mRNA，导致剪接的 XBP-1 (XBP-1s) mRNA 编码功能性 XBP-1s 转录因子，这对 B 的生长和存活至关重要-细胞白血病、淋巴瘤和多发性骨髓瘤 (MM)。已经报道了几种靶向 XBP-1 表达的抑制剂；然而，每种抑制剂对癌细胞的细胞毒性变化很大。为了设计更好的 B 细胞癌治疗策略，我们系统地比较了这些化合物在体外抑制 IRE-1 RNase 活性和抑制 XBP-1s 在小鼠和人类 MM 细胞系中表达的能力。基于三环色烯酮的抑制剂 B-I09 和 D-F07，含有醛掩蔽基团的前药，成为有效抑制 MM 细胞中 XBP-1s 表达的最可靠抑制剂。B-I09 和 D-F07 对 MM 以及慢性淋巴细胞白血病和套细胞淋巴瘤的细胞毒性可以通过与 PI3K/AKT 途径的抑制剂组合进一步增强。由于水杨醛羟基的化学修饰可用于调节 1,3-二恶烷前药的稳定性，我们在这些抑制剂上安装了活性氧敏感的结构笼基团，以实现刺激响应活性并提高肿瘤靶向效率。