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

Authors :
Qin, Jingbo
Chen, Xiaohui
Liu, Weihao
Chen, Jun
Liu, Weirong
Xia, Yongzhen
Li, Zhehui
Li, Mingyu
Wang, Shaojuan
Yuan, Quan
Qiu, Yingkun
Wu, Zhen
Fang, Meijuan
Source :
European Journal of Medicinal Chemistry. Dec2022, Vol. 244, pN.PAG-N.PAG. 1p.
Publication Year :
2022

Abstract

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. [Display omitted] • New 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives are synthesized. • 8b is a good binder of Nur77 (K D = 354 nM) with broad-spectrum antitumor activity. • 8b induces Nur77-targeting mitochondria and Nur77-dependent apoptosis. • 8b displays a better safety than reference compound celastrol in vitro and in vivo. • 8b effectively inhibits tumor growth in a mice hepatoma HepG2 xenograft model. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02235234
Volume :
244
Database :
Academic Search Index
Journal :
European Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
160213634
Full Text :
https://doi.org/10.1016/j.ejmech.2022.114849