Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of nextgeneration therapeutics to manage advanced PCa.
|Number of pages||17|
|Early online date||4 Oct 2017|
|Publication status||Published - Nov 2017|
- Androgen Receptor (AR)
- Selective Androgen Receptor Degraders (SARDs)
- AR Splice Variants (AR-SV)
- prostate cancer
- Castration-Resistant Prostate Cancer (CRPC)
- AR antagonist
- AF-1-binding AR antagonist
- AR translocation inhibitor
- AR pan-antagonist
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- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Personal Chair
- Institute of Medical Sciences