TY - JOUR
T1 - Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer
AU - Ponnusamy, Suriyan
AU - Coss, Christopher C.
AU - Thiyagarajan, Thirumagal
AU - Watts, Kate
AU - Hwang, Dong Jin
AU - He, Yali
AU - Selth, Luke A.
AU - McEwan, Iain J.
AU - Duke, Charles B.
AU - Pagadala, Jayaprakash
AU - Singh, Geetika
AU - Wake, Robert W.
AU - Ledbetter, Christopher
AU - Tilley, Wayne D.
AU - Moldoveanu, Tudor
AU - Dalton, James T.
AU - Miller, Duane D.
AU - Narayanan, Ramesh
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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 ubi-quitinated 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.
AB - 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 ubi-quitinated 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.
KW - Prostate Cancer
KW - Androgen receptor
UR - http://www.scopus.com/inward/record.url?scp=85033771016&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0976
DO - 10.1158/0008-5472.CAN-17-0976
M3 - Article
C2 - 28978635
AN - SCOPUS:85033771016
SN - 0008-5472
VL - 77
SP - 6282
EP - 6298
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -