The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347–2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC50 values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC50 values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.

中文翻译：

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4-（4-（3-（1-（2--（哌啶-1-基）乙基）-1H-苯并[d]咪唑-2-基）异噁唑-5-基）苯基）吗啉作为一种新型 c-Myc 抑制剂的发现


c-Myc 作为肺癌发展发展的关键因素，使其成为抗肺癌治疗研究的关键靶点。在我们之前的研究中，我们报道了 D347-2761 的发现，这是一种新型小分子抑制剂，专门靶向 c-Myc 的不稳定结构域并破坏 c-Myc/Max 异二聚体。为了进一步加强靶向治疗，我们进行了广泛的结构分析并设计了一系列创新的苯并咪唑衍生物。使用 CCK-8 测定评估这些化合物的细胞毒活性，显示化合物 A1 对 A549 和 NCI-H1299 肺癌细胞系的 IC50 值分别为 6.32 μM 和 11.39 μM，而化合物 A5 对相同细胞系的 IC50 值为 4.08 μM 和 7.86 μM。我们的研究结果显示，化合物 A1 和 A5 通过破坏 c-Myc 和 Max 蛋白之间的相互作用表现出强大的抗癌活性，导致 c-Myc 蛋白水平下调并通过凋亡途径诱导细胞凋亡。值得注意的是，与其他测试化合物相比，化合物 A5 表现出优异的抑制能力。此外，在同基因肿瘤模型中，化合物 A5 表现出优异的疗效，肿瘤生长抑制率高达 76.4%，同时 c-Myc 蛋白表达水平显著降低。因此，化合物 A5 有望成为抗肺癌治疗中靶向 c-Myc 的潜在药物。