Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.
Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.
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DOI：
10.1002/anie.201503720
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发表时间：
2015-08-10
期刊：
影响因子：
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通讯作者：
Crews CM
中科院分区：
文献类型：
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作者：
Gustafson JL;Neklesa TK;Cox CS;Roth AG;Buckley DL;Tae HS;Sundberg TB;Stagg DB;Hines J;McDonnell DP;Norris JD;Crews CM
雄激素受体(AR)依赖的转录是前列腺肿瘤细胞增殖的主要驱动力。因此，它是几种抗肿瘤化疗药物的靶点，包括AR拮抗剂MDV3100/苯扎鲁胺。最近的研究表明，单个AR突变(F876L)可以将MDV3100的作用从拮抗剂转变为激动剂。在这里，我们描述了一类新的选择性雄激素受体降解物(SARD)的产生，以解决这种耐药机制。含有与雄激素受体(AR)小分子配体相连的疏水变性的分子可诱导AR降解，减少AR靶基因的表达，并抑制雄激素依赖型前列腺癌细胞系的增殖。这些结果表明，选择性AR降解在AR突变的背景下可能是一种有效的治疗前列腺癌的策略，该突变使人对第三代AR拮抗剂产生耐药性。
Androgen Receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of Selective Androgen Receptor Degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small molecule Androgen Receptor (AR) ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to third generation AR antagonists.