Encouraged by our previous findings and in continuation of our ongoing study project in designing and synthesis of novel Nur77-targeting anti-cancer agents, a series of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives were designed, synthesized and biologically evaluated as potent Nur77 modulators. Among synthesized compounds, 8b maintained good potency against different liver cancer cell lines and other types of cancer cell lines while exhibiting lower toxicity than the positive compound celastrol. Moreover, 8b displayed excellent Nur77-binding activity, superior to the lead compound 10g and comparable to the reference compound celastrol. The cytotoxic action of 8b towards cancer cells was associated with its induction of Nur77-mitochondrial targeting and Nur77-dependent apoptosis. Notably, 8b has good in vivo safety and anti-hepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.

受到我们之前发现的鼓舞，并继续我们正在进行的设计和合成新型 Nur77 靶向抗癌剂的研究项目，一系列 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino )-1H-indole-2-carboxamide 衍生物被设计、合成并作为有效的 Nur77 调节剂进行了生物学评估。在合成的化合物中，8b对不同的肝癌细胞系和其他类型的癌细胞系保持良好的效力，同时表现出比阳性化合物 celastrol 更低的毒性。此外，8b显示出优异的 Nur77 结合活性，优于先导化合物10g，与参考化合物 celastrol 相当。8b的细胞毒作用对癌细胞的作用与其诱导 Nur77 线粒体靶向和 Nur77 依赖性细胞凋亡有关。值得注意的是，8b具有良好的体内安全性和抗肝细胞癌 (HCC) 活性。总而言之，这项研究表明8b是一种新型 Nur77 调制器，有望进一步研究。