Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan.
Department of Biochemistry and Molecular Biology, Chang Gung University, Taoyuan 33302, Taiwan.
EBioMedicine. 2023 Apr;90:104500. doi: 10.1016/j.ebiom.2023.104500. Epub 2023 Mar 7.
Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance.
We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker.
In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy.
AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance.
The funding detail can be found in the Acknowledgements section.
尽管有了改善的治疗选择，晚期前列腺癌的疗效持续时间仍然有限，因为不可避免地会产生耐药性。由于配体结合结构域截断的雄激素受体（AR）变体（AR-V（ΔLBD））持续维持雄激素受体信号，这是导致对抗雄激素药物产生耐药性的主要机制。需要针对 AR 和其 LBD 截断变体的策略来预防耐药性的出现或克服耐药性。
我们利用蛋白水解靶向嵌合体（PROTAC）技术来实现全长 AR（AR-FL）和 AR-V（ΔLBD）蛋白的诱导降解。在 ITRI-PROTAC 设计中，AR N 端结构域（NTD）结合部分与 von-Hippel-Lindau（VHL）或 Cereblon（CRBN）E3 连接酶结合配体相连。
体外研究表明，ITRI-PROTAC 化合物通过泛素-蛋白酶体系统，在机制上降解 AR-FL 和 AR-V（ΔLBD）蛋白，导致 AR 对靶基因表达的转录激活受损，以及细胞增殖抑制和凋亡激活。这些化合物还显著抑制去势抵抗性前列腺癌（CRPC）细胞的恩扎卢胺耐药生长。在去势、恩扎卢胺耐药的 CWR22Rv1 异种移植模型中，没有激素消融，ITRI-90 显示出具有良好口服生物利用度和强大抗肿瘤功效的药代动力学特征。
AR NTD 控制所有活性变体的转录活性，被认为是阻断前列腺癌细胞中 AR 信号的有吸引力的治疗靶点。我们证明，利用 PROTAC 通过 NTD 诱导 AR 蛋白降解代表了克服抗雄激素耐药性的 CRPC 的有效替代治疗策略。
资助详情见致谢部分。
