American Association for Cancer Research
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Supporting Figures S1-S4 from Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer

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posted on 2023-03-31, 01:08 authored by Suriyan Ponnusamy, Christopher C. Coss, Thirumagal Thiyagarajan, Kate Watts, Dong-Jin Hwang, Yali He, Luke A. Selth, Iain J. McEwan, Charles B. Duke, Jayaprakash Pagadala, Geetika Singh, Robert W. Wake, Christopher Ledbetter, Wayne D. Tilley, Tudor Moldoveanu, James T. Dalton, Duane D. Miller, Ramesh Narayanan

S1: SARDs inhibit AR mutant activity. S2: UT-155-dependent degradation is selective to the AR. S3: UT-155 degrades wildtype and Y267 phospho mutant ARs. S4. UT-155 inhibits AR ABCD and AR-V7 induced activity.


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Androgen receptor (AR) mediates the growth of prostate cancer 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 prostate cancer 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 (SARD) that markedly reduce the activity of wild-type and splice variant isoforms of AR at submicromolar 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 next-generation therapeutics to manage advanced prostate cancer. Cancer Res; 77(22); 6282–98. ©2017 AACR.

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