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Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Author(s) -
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.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201503720
Subject(s) - androgen receptor , enzalutamide , prostate cancer , context (archaeology) , agonist , chemistry , cancer research , small molecule , antagonist , androgen , androgen receptor antagonists , lncap , transcription factor , receptor , hek 293 cells , mechanism of action , microbiology and biotechnology , biology , biochemistry , cancer , gene , in vitro , genetics , hormone , paleontology
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.