Details

Autor(en) / Beteiligte

• Gustafson, Jeffrey L.
• Neklesa, Taavi K.
• Cox, Carly S.
• Roth, Anke G.
• Buckley, Dennis L.
• Tae, Hyun Seop
• Sundberg, Thomas B.
• Stagg, D. Blake
• Hines, John
• McDonnell, Donald P.
• Norris, John D.
• Crews, Craig M.

Titel

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

Ist Teil von

• Angewandte Chemie (International ed.), 2015-08, Vol.54 (33), p.9659-9662

Auflage

International ed. in English

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Making the problem go away: Most prostate tumor growth is driven by the action of the androgen receptor (AR). Resistance to current chemotherapies for prostate cancer can occur when the androgen receptor is either overexpressed or mutated. Coupling of an AR agonist to an adamantyl “hydrophobic tag” resulted in a molecule that induces AR degradation, even in drug‐resistant prostate tumor cells.