Multivalent peptidomimetic conjugates: A versatile platform for modulating androgen receptor activity

Paul M. Levine; Keren Imberg; Michael J. Garabedian; Kent Kirshenbaum

doi:10.1021/ja300170n

Multivalent peptidomimetic conjugates: A versatile platform for modulating androgen receptor activity

Paul M. Levine, Keren Imberg, Michael J. Garabedian, Kent Kirshenbaum

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	6912-6915
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	134
Issue number	16
DOIs	https://doi.org/10.1021/ja300170n
State	Published - Apr 25 2012

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

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10.1021/ja300170n

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abstract = "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.",

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AU - Levine, Paul M.

AU - Imberg, Keren

AU - Garabedian, Michael J.

AU - Kirshenbaum, Kent

PY - 2012/4/25

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AB - 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.

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Multivalent peptidomimetic conjugates: A versatile platform for modulating androgen receptor activity

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