title: A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro.
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.
authors.affiliation: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, PR China.
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Liu
authors.forename: Hui-ni
authors.initials: HN
authors.lastname: Zeng
authors.forename: Lian-ru
authors.initials: LR
authors.lastname: Zhang
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Zhan
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Shao-hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Wen-jun
authors.initials: WJ
authors.lastname: Liu
authors.forename: Wei-jia
authors.initials: WJ
authors.lastname: Wang
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Yue-mao
authors.initials: YM
authors.lastname: Shen
authors.forename: Wen-jin
authors.initials: WJ
authors.lastname: Su
authors.forename: Pei-qiang
authors.initials: PQ
authors.lastname: Huang
authors.forename: Hong-kui
authors.initials: HK
authors.lastname: Zhang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C091514:BABAM2 protein, human; C539821:NR4A1 protein, human; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; C531461:cytosporone B