A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro
A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro
复制标题
用于在体内和体外激活核孤儿受体 Nur77 的独特药效基团
DOI：
10.1158/0008-5472.can-09-3160
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Liu, Jing-jing;Zeng, Hui-ni;Wu, Qiao
Nur 77是一种类固醇孤儿受体，在调节增殖、分化和凋亡中起关键作用，包括充当Bcl-2功能的开关。我们以前报道过，octaketide cytosporone B（Csn-B）是Nur 77的天然激动剂。在这项研究中，我们合成了一系列Csn-B类似物，并进行了结构-活性分析，提出了一个独特的药效团激活Nur 77的发展标准。结合Nur 77所需的药效团的组分包括苯环、酚羟基和Csn-B支架的酰基链，而激活Nur 77生物功能的关键特征是酯基。与Nur 77紧密结合的Csn-B类似物不仅刺激其反式激活活性，而且通过Nur 77与BRE（一种在转录水平上调节的抗凋亡蛋白）之间的新型串扰启动线粒体凋亡。值得注意的是，衍生物2-[3，5-二羟基-2-（1-壬酰基）苯基]乙酸正戊酯表现出比其母体化合物更大的体内抗肿瘤活性，突出了对该化合物的特别关注。我们的研究结果描述了一种合理设计Csn-B衍生的Nur 77激动剂作为一类新的强效和有效的抗肿瘤药物的途径。Cancer Res; 70（9）; 3628-37. (C)2010年AACR。
Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel crosstalk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl] acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents. Cancer Res; 70(9); 3628-37. (C) 2010 AACR.