A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro

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...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2010-05, Vol.70 (9), p.3628-3637
Main Authors: LIU, Jing-Jing, ZENG, Hui-Ni, CHEN, Hang-Zi, SHEN, Yue-Mao, SU, Wen-Jin, HUANG, Pei-Qiang, ZHANG, Hong-Kui, QIAO WU, ZHANG, Lian-Ru, ZHAN, Yan-Yan, YAN CHEN, YUAN WANG, JUAN WANG, XIANG, Shao-Hua, LIU, Wen-Jun, WANG, Wei-Jia
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Drug Delivery Systems
Humans
Male
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Models, Molecular
Molecular Conformation
Nerve Tissue Proteins - metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1 - agonists
Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism
Pharmacology. Drug treatments
Phenylacetates - chemistry
Phenylacetates - pharmacology
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Structure-Activity Relationship
Transcription, Genetic - drug effects
Tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-09-3160