Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer.
Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer.
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DOI：
10.1016/j.ebiom.2023.104500
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发表时间：
2023-04
期刊：
影响因子：
11.1
通讯作者：
Wang, Ling-Yu
中科院分区：
文献类型：
--
作者：
Hung, Chiu-Lien;Liu, Hao-Hsuan;Fu, Chih-Wei;Yeh, Hsun-Hao;Hu, Tsan-Lin;Kuo, Zong-Keng;Lin, Yu-Chin;Jhang, Mei-Ru;Hwang, Chrong-Shiong;Hsu, Hung-Chih;Kung, Hsing-Jien;Wang, Ling-Yu
尽管针对晚期前列腺癌出现了改进的治疗选择，但由于不可避免的耐药性的发展，临床益处的持久性受到限制。通过组成性维持雄激素受体 (AR) 信号传导，配体结合域截短的 AR 变体 (AR-V(ΔLBD)) 的表达是抗雄激素药物耐药的主要机制。需要针对 AR 及其 LBD 截短变体的策略来防止出现或克服耐药性。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 末端结构域 (NTD) 结合部分通过接头附加到 von-Hippel-Lindau (VHL) 或 Cereblon (CRBN) E3 连接酶结合配体上。体外研究表明，ITRI-PROTAC 化合物通过泛素蛋白酶体系统机械地降解 AR-FL 和 AR-V(ΔLBD) 蛋白，导致靶基因表达的 AR 反式激活受损，并抑制细胞增殖并伴随凋亡激活。这些化合物还显着抑制去势抵抗性前列腺癌（CRPC）细胞的恩杂鲁胺抵抗性生长。在无激素消融的去势、恩杂鲁胺耐药性 CWR22Rv1 异种移植模型中，ITRI-90 显示出具有良好口服生物利用度和强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 信号传导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 CRPC 克服抗雄激素耐药性的有效替代治疗策略。资助详细信息可以在致谢部分找到。
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.
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影响因子：
7.3
作者：
Han X;Zhao L;Xiang W;Qin C;Miao B;McEachern D;Wang Y;Metwally H;Wang L;Matvekas A;Wen B;Sun D;Wang S
通讯作者：
Wang S
组成型活性雄激素受体剪接变体AR-V3，AR-V7和AR-V9在castration抗性的前列腺癌转移中共表达。
影响因子：
8.8
作者：
Kallio HML;Hieta R;Latonen L;Brofeldt A;Annala M;Kivinummi K;Tammela TL;Nykter M;Isaacs WB;Lilja HG;Bova GS;Visakorpi T
通讯作者：
Visakorpi T
DOI：
10.1158/1078-0432.ccr-17-0017
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kohli M;Ho Y;Hillman DW;Van Etten JL;Henzler C;Yang R;Sperger JM;Li Y;Tseng E;Hon T;Clark T;Tan W;Carlson RE;Wang L;Sicotte H;Thai H;Jimenez R;Huang H;Vedell PT;Eckloff BW;Quevedo JF;Pitot HC;Costello BA;Jen J;Wieben ED;Silverstein KAT;Lang JM;Wang L;Dehm SM
通讯作者：
Dehm SM
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
78.5
作者：
Bartlett, JB;Dredge, K;Dalgleish, AG
通讯作者：
Dalgleish, AG