Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor
Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor
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DOI：
10.1016/j.ccr.2010.04.027
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发表时间：
2010-06-15
期刊：
影响因子：
50.3
通讯作者：
Sadar, Marianne D.
中科院分区：
文献类型：
--
作者：
Andersen, Raymond J.;Mawji, Nasrin R.;Sadar, Marianne D.
去势复发性前列腺癌(CRPC)可能依赖雄激素受体(AR)。AR氨基末端结构域(NTD)中的AF-1区域包含大部分转录活性，如果不是全部的话。在这里，我们确定了EPI-001，一个小分子，阻止NTD的反式激活，在不减弱相关类固醇受体转录活性的情况下，特异性地抑制AR。EPI-001与AF-1区域相互作用，抑制与AR的蛋白质-蛋白质相互作用，并减少AR与靶基因上雄激素反应元件的相互作用。重要的是，EPI-001阻断了雄激素诱导的增殖，并导致依赖AR生长和存活的异种移植物中CRPC的细胞减少，而不会造成毒性。
Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.