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Angew Chem Int Ed Engl. 2015 Aug 10;54(33):9659-62. doi: 10.1002/anie.201503720. Epub 2015 Jun 17.

Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

Author information

1
Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA).
2
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 (USA).
3
Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University, New Haven, CT 065111 (USA). craig.crews@yale.edu.

Abstract

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 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 second-generation AR antagonists.

KEYWORDS:

antiproliferation; cancer; drug design; hormones; protein degradation

PMID:
26083457
PMCID:
PMC4547777
DOI:
10.1002/anie.201503720
[Indexed for MEDLINE]
Free PMC Article

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