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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gustafson, JL; Neklesa, TK; Cox, CS; Roth, AG; Buckley, DL; Tae, HS; Sundberg, TB; Stagg, DB; Hines, J; McDonnell, DP; Norris, JD; Crews, CM

Published Date

  • August 10, 2015

Published In

Volume / Issue

  • 54 / 33

Start / End Page

  • 9659 - 9662

PubMed ID

  • 26083457

Pubmed Central ID

  • PMC4547777

Electronic International Standard Serial Number (EISSN)

  • 1521-3773

Digital Object Identifier (DOI)

  • 10.1002/anie.201503720


  • eng

Conference Location

  • Germany