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Identification of neuron selective androgen receptor inhibitors

Identification of neuron selective androgen receptor inhibitors

作     者:Maya Otto-Duessel Ben Yi Tew Steven Vonderfecht Roger Moore Jeremy O Jones 

作者机构:Department of Cancer Biology Beckman Research Institute City of Hope National Medical Center Division of Comparative Medicine Beck-man Research Institute City of Hope National Medical Center Department of Molecular Immunology Beckman Research Institute City of Hope National Medical Center 

出 版 物:《World Journal of Biological Chemistry》 (世界生物化学杂志(英文版)(电子版))

年 卷 期:2017年第8卷第2期

页      面:138-150页

学科分类:1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

主  题:Androgen receptor Selective androgen receptor modulator Spinal and bulbar muscular atrophy Kennedy’s disease 

摘      要:AIM To identify neuron-selective androgen receptor(AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy(SBMA), or Kennedy s disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell typeselective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuronselective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-q PCR of AR-regulated genes and *** We identified the thiazole class of antibiotics as com-pounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that sh RNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the associa

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