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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.

Alternative Inhibition of Androgen Receptor Signaling: Peptidomimetic Pyrimidines As Direct Androgen Receptor/Coactivator Disruptors