Multivalent Peptidomimetic Conjugates: A Versatile Platform for Modulating Androgen Receptor Activity

被引：63
作者：
Levine, Paul M. [1 ]
Imberg, Keren [2 ]
Garabedian, Michael J. [3 ]
Kirshenbaum, Kent [1 ]
机构：
[1] NYU, Dept Chem, New York, NY 10003 USA
[2] NYU, Langone Sch Med, Dept Pharmacol, New York, NY 10016 USA
[3] NYU, Langone Sch Med, Dept Microbiol, New York, NY 10016 USA
来源：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2012年 / 134卷 / 16期
关键词：
PROSTATE-CANCER; STRUCTURAL BASIS; ANTIANDROGEN; COACTIVATOR; RESISTANCE; PEPTOIDS; AGONIST; BICALUTAMIDE; DIMERIZATION; STEROIDS;
D O I：
10.1021/ja300170n
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.
引用
收藏
页码：6912 / 6915
页数：4
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