Development of Small Molecular Hyper-activators of Human Caseinolytic Peptidase P (hClpP) with a [1,8]-Naphthyridinone Scaffold as Novel Anti-cancer Agents.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-11-06 DOI:10.1002/cmdc.202400528

Haiying Sun, Yuantao Fu, Yinan Yuan, Rongliang Tan, Jinxin Jiang, Zhilong Li, Tong Li, Guangjun Xie, Yibei Xiao

引用次数: 0

Abstract

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold were designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

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开发具有 [1,8]- 萘啶酮支架的人酪蛋白溶解肽酶 P (hClpP) 小分子超活化剂，作为新型抗癌药物。

以临床阶段的小分子 hClpP 激活剂 ONC201 为基础，设计、合成并在一系列生化和生物学实验中评估了一类具有 [1,8]naphthyridinone 支架的新型 hClpP 激动剂。代表性化合物 F20 的机理研究表明，它能有效地与 hClpP 结合并激活 hClpP，有效地促进 hClpP 底物的降解，强有力地诱导 ATF4/CHOP 调节的综合应激反应，强烈抑制细胞生长，并有效地诱导特定癌细胞株的凋亡。F20 在静脉注射时显示出良好的 PK 曲线，并在小鼠体内表现出适度的口服生物利用度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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