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

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 stra

SUBMITTER: Gustafson JL 

PROVIDER: S-EPMC4547777 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature