Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.
Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.
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DOI：
10.1038/nchembio.2131
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发表时间：
2016-10
影响因子：
14.8
通讯作者：
Norris JD
中科院分区：
文献类型：
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作者：
Pollock JA;Wardell SE;Parent AA;Stagg DB;Ellison SJ;Alley HM;Chao CA;Lawrence SA;Stice JP;Spasojevic I;Baker JG;Kim SH;McDonnell DP;Katzenellenbogen JA;Norris JD
尽管肿瘤中存在持久的雄激素受体(AR)活性，但第二代抗雄激素药物苯扎鲁胺在抗去势前列腺癌(CRPC)中的临床耐药性突显了对下一代拮抗剂的医学需求尚未得到满足。我们已经确定并表征了四芳基环丁烷(CBS)，它是一类新型竞争性AR拮抗剂，具有独特的作用机制。这些CBS在结构上不同于目前的抗雄激素(羟基氟他胺、比卡鲁胺和苯扎鲁胺)，并在几种CRPC模型中抑制AR介导的基因表达、细胞增殖和肿瘤生长。构象分析显示，CBS稳定AR构象，类似于未连接的受体。使用各种技术，确定AR：CB复合体没有被AR调节的启动子招募，并且像载脂蛋白AR一样，仍然隔离在与热休克蛋白结合的细胞质中。因此，我们已经确定了第三代AR拮抗剂，其独特的作用机制表明它们可能在CRPC中具有治疗潜力。
Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.