Discovery of 5-((4-(pyridin-3-yl)pyrimidin-2-yl) amino)-1H-indole-2-carboxamide derivatives as novel anti-cancer agents targeting Nur77

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-2carboxamide 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 Nur77mitochondrial targeting and Nur77-dependent apoptosis. Notably, 8b has good in vivo safety and antihepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.

Automated summary

In this study, a series of novel Nur77 modulators were designed, synthesized, and evaluated for their anti-cancer activity. Compound 8b exhibited potent activity against various cancer cell lines, including liver cancer cells, with lower toxicity than the positive compound celastrol. Moreover, 8b showed excellent Nur77-binding activity and demonstrated good safety and anti-hepatocellular carcinoma (HCC) activity in vivo.