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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

Jing-jing Liu, Hui-ni Zeng, Lian-ru Zhang, Yan-yan Zhan, Yan Chen, Yuan Wang, Juan Wang, Shao-hua Xiang, Wen-jun Liu, Wei-jia Wang, Hang-zi Chen, Yue-mao Shen, Wen-jin Su, Pei-qiang Huang, Hong-kui Zhang, etc.

Cancer Res. 2010 May 1;70(9):3628-37.

PMID: 20388790

Abstract:

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 cross-talk 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4242064	n-Amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate			Price

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