Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
Mol Cancer Ther. 2021 Mar;20(3):490-499. doi: 10.1158/1535-7163.MCT-20-0417. Epub 2020 Dec 4.
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% (DC) 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 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.
虽然二线抗雄激素治疗（SAT）是去势抵抗性前列腺癌（CRPC）患者的标准治疗方法，但不可避免地会出现耐药性。一种主要的耐药机制涉及雄激素受体（AR）剪接变体 7（AR-V7）的出现。最近，我们使用蛋白水解靶向嵌合体（PROTAC）的原理开发了 MTX-23，以靶向 AR-V7 和 AR 全长（AR-FL）。MTX-23 的设计目的是同时结合 AR 的 DNA 结合域（DBD）和 von Hippel-Lindau（VHL）E3 泛素连接酶。免疫印迹表明，MTX-23 对 AR-V7 和 AR-FL 的降解浓度 50%（DC）分别为 0.37 和 2 μmol/L。进一步的研究表明，MTX-23 仅在雄激素反应性前列腺癌细胞中抑制前列腺癌细胞增殖并增加细胞凋亡。当过表达 AR-V7 或 AR-FL 时，MTX-23 的抗增殖作用部分逆转，当两者均过表达时，该作用完全被消除。为了评估 MTX-23 的潜在治疗价值，我们接下来生成了 12 种对四种 FDA 批准的 SAT 药物（阿比特龙、恩杂鲁胺、阿帕鲁胺和达罗鲁胺）耐药的人前列腺癌细胞系。当耐药细胞用 MTX-23 处理时，在人和小鼠中均观察到细胞增殖减少和肿瘤生长减少。这些结果共同表明，MTX-23 是一种新型 PROTAC 小分子，通过降解 AR-V7 和 AR-FL，可能对 SAT 耐药的 CRPC 有效。
