TY - JOUR
T1 - Alternative inhibition of androgen receptor signaling
T2 - Peptidomimetic pyrimidines as direct androgen receptor/coactivator disruptors
AU - Gunther, Jillian R.
AU - Parent, Alexander A.
AU - Katzenellenbogen, John A.
PY - 2009/6/19
Y1 - 2009/6/19
N2 - Compounds that directly disrupt the androgen receptor/steroid receptor coactivator interaction could function as novel inhibitors of androgen signaling that would remain effective in the treatment of prostate cancer that is resistant to conventional endocrine therapies. A structure-based peptidomimetic approach was used to design and synthesize such compounds, based on a pyrimidine-core system. Using fluorescence resonance energy transfer and reporter gene assays, we identified members of this library that disrupt the androgen receptor/steroid receptor coactivator interaction selectively, without affecting the estrogen receptor/steroid receptor coactivator interaction. Unlike the activity of traditional androgen receptor antagonists, such as flutamide and bicalutamide, inhibition by these coactivator binding inhibitors is insurmountable by increased concentrations of androgen agonists and maintains effectiveness even on a mutant androgen receptor that is resistant to traditional antagonists. These findings support the feasibility of targeting the coactivator binding groove of the androgen receptor as an alternative approach to treatment-resistant prostate cancer therapy.
AB - Compounds that directly disrupt the androgen receptor/steroid receptor coactivator interaction could function as novel inhibitors of androgen signaling that would remain effective in the treatment of prostate cancer that is resistant to conventional endocrine therapies. A structure-based peptidomimetic approach was used to design and synthesize such compounds, based on a pyrimidine-core system. Using fluorescence resonance energy transfer and reporter gene assays, we identified members of this library that disrupt the androgen receptor/steroid receptor coactivator interaction selectively, without affecting the estrogen receptor/steroid receptor coactivator interaction. Unlike the activity of traditional androgen receptor antagonists, such as flutamide and bicalutamide, inhibition by these coactivator binding inhibitors is insurmountable by increased concentrations of androgen agonists and maintains effectiveness even on a mutant androgen receptor that is resistant to traditional antagonists. These findings support the feasibility of targeting the coactivator binding groove of the androgen receptor as an alternative approach to treatment-resistant prostate cancer therapy.
UR - http://www.scopus.com/inward/record.url?scp=67649283584&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67649283584&partnerID=8YFLogxK
U2 - 10.1021/cb900043e
DO - 10.1021/cb900043e
M3 - Article
C2 - 19441848
AN - SCOPUS:67649283584
SN - 1554-8929
VL - 4
SP - 435
EP - 440
JO - ACS chemical biology
JF - ACS chemical biology
IS - 6
ER -