雄激素
LNCaP公司
内科学
抗雄激素
雄激素受体拮抗剂
比卡鲁胺
内分泌学
生物
二氢睾酮
受体
核受体
抗雄激素
作者
Geun Taek Lee,Naoya Nagaya,Jenny Desantis,Kiran Madura,Hatem E. Sabaawy,Wun-Jae Kim,Roy J. Vaz,Gabriele Cruciani,Isaac Yi Kim
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2021-03-01
卷期号:20 (3): 490-499
被引量:11
标识
DOI:10.1158/1535-7163.mct-20-0417
摘要
Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.
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