前列腺癌中蛋白酶体依赖性雄激素受体降解的机制与靶向作用
Mechanisms and targeting of proteosome-dependent androgen receptor degradation in prostate cancer.
作者信息
Fang Qinghua, Cole Ryan N, Wang Zhou
机构信息
Department of Urology, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA.
出版信息
Am J Clin Exp Urol. 2022 Dec 25;10(6):366-376. eCollection 2022.
Abstract
The androgen receptor (AR) remains to be a key target for the treatment of prostate cancer, including the majority of castration-resistant prostate cancer (CRPC). AR is stabilized in CRPC and the ubiquitin-proteasome system (UPS) plays a major role in AR degradation. Targeting AR for degradation provides a potential approach to overcome the resistance of CRPC to current AR antagonists, including the next generation AR signaling inhibitors. Different types of AR degraders have been developed, including the proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), and novel AR degraders, with several AR PROTACs currently in clinical trials. The present mini-review discusses the regulation of AR degradation by the UPS, the potential role of a novel nuclear degradation signal in AR, and different types of AR degraders.
摘要
雄激素受体（AR）仍然是前列腺癌治疗的关键靶点，包括大多数去势抵抗性前列腺癌（CRPC）。在CRPC中AR是稳定的，泛素 - 蛋白酶体系统（UPS）在AR降解中起主要作用。靶向AR进行降解为克服CRPC对当前AR拮抗剂（包括下一代AR信号抑制剂）的耐药性提供了一种潜在方法。已经开发了不同类型的AR降解剂，包括蛋白酶体靶向嵌合体（PROTAC）、选择性AR降解剂（SARD）和新型AR降解剂，目前有几种AR PROTAC正在进行临床试验。本综述讨论了UPS对AR降解的调节、AR中新型核降解信号的潜在作用以及不同类型的AR降解剂。
相似文献
1
Mechanisms and targeting of proteosome-dependent androgen receptor degradation in prostate cancer.前列腺癌中蛋白酶体依赖性雄激素受体降解的机制与靶向作用
Am J Clin Exp Urol. 2022 Dec 25;10(6):366-376. eCollection 2022.
2
A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives.小分子雄激素受体降解剂综述：最新进展与未来展望
J Med Chem. 2022 Dec 22;65(24):16128-16154. doi: 10.1021/acs.jmedchem.2c01487. Epub 2022 Dec 2.
3
Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer.去势抵抗性前列腺癌中雄激素受体降解的最新进展洞察
Cancers (Basel). 2024 Feb 4;16(3):663. doi: 10.3390/cancers16030663.
4
An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.新一代雄激素受体靶向治疗药物治疗前列腺癌的概述。
Int J Mol Sci. 2021 Feb 20;22(4):2124. doi: 10.3390/ijms22042124.
5
PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer.PROTACs作为去势抵抗性前列腺癌药物研发的治疗方式
Annu Rev Pharmacol Toxicol. 2025 Jan;65(1):375-396. doi: 10.1146/annurev-pharmtox-030624-110238. Epub 2024 Dec 17.
6
Targeting androgen receptor degradation with PROTACs from bench to bedside.利用 PROTAC 靶向雄激素受体降解：从实验室到临床。
Biomed Pharmacother. 2023 Feb;158:114112. doi: 10.1016/j.biopha.2022.114112. Epub 2022 Dec 9.
7
Improving Strategies in the Development of Protein-Downregulation-Based Antiandrogens.基于下调蛋白质的抗雄激素药物开发的改进策略。
ChemMedChem. 2021 Jul 6;16(13):2021-2033. doi: 10.1002/cmdc.202100033. Epub 2021 Apr 23.
8
Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer.布鲁斯汀通过靶向 HSP90 克服去势抵抗性前列腺癌对激素治疗的耐药性。
Theranostics. 2021 Jan 1;11(2):958-973. doi: 10.7150/thno.51478. eCollection 2021.
9
Interference with the androgen receptor protein stability in therapy-resistant prostate cancer.治疗抵抗性前列腺癌中雄激素受体蛋白稳定性的干扰。
Int J Cancer. 2019 Apr 15;144(8):1775-1779. doi: 10.1002/ijc.31818. Epub 2018 Nov 4.
10
Targeting GRP78-dependent AR-V7 protein degradation overcomes castration-resistance in prostate cancer therapy.靶向 GRP78 依赖性 AR-V7 蛋白降解克服前列腺癌治疗中的去势抵抗。
Theranostics. 2020 Feb 10;10(8):3366-3381. doi: 10.7150/thno.41849. eCollection 2020.
引用本文的文献
1
Neuregulin-1 correlates to early castration-resistant prostate cancer after prostate cancer patients receiving androgen deprivation therapy.在前列腺癌患者接受雄激素剥夺治疗后，神经调节蛋白-1与早期去势抵抗性前列腺癌相关。
J Cancer. 2025 Jul 11;16(10):3261-3269. doi: 10.7150/jca.112954. eCollection 2025.
2
UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer.UBX-390：一种新型雄激素受体降解剂，可用于前列腺癌的治疗干预。
Adv Sci (Weinh). 2024 Sep;11(33):e2400398. doi: 10.1002/advs.202400398. Epub 2024 Jul 3.
3
Regulation of androgen receptor stability by the β Pix/STUB1 complex.β Pix/STUB1复合物对雄激素受体稳定性的调节。
FASEB J. 2024 Feb;38(2):e23408. doi: 10.1096/fj.202301100R.
4
Therapeutic potential of natural antisense transcripts and various mechanisms involved for clinical applications and disease prevention.天然反义转录本的治疗潜力及其在临床应用和疾病预防中的各种相关机制。
RNA Biol. 2024 Jan;21(1):1-18. doi: 10.1080/15476286.2023.2293335. Epub 2023 Dec 13.
5
PROTACs: A novel strategy for cancer drug discovery and development.PROTACs：癌症药物发现与开发的新策略。
MedComm (2020). 2023 May 29;4(3):e290. doi: 10.1002/mco2.290. eCollection 2023 Jun.
6
Let's Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer.让我们进入 3D 时代！新一代模型用于评估前列腺癌中的药物反应和耐药性。
Int J Mol Sci. 2023 Mar 10;24(6):5293. doi: 10.3390/ijms24065293.
本文引用的文献
1
A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives.小分子雄激素受体降解剂综述：最新进展与未来展望
J Med Chem. 2022 Dec 22;65(24):16128-16154. doi: 10.1021/acs.jmedchem.2c01487. Epub 2022 Dec 2.
2
SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer.SPOP 突变作为去势敏感性转移性前列腺癌中雄激素受体轴靶向治疗的预测生物标志物。
Clin Cancer Res. 2022 Nov 14;28(22):4917-4925. doi: 10.1158/1078-0432.CCR-22-2228.
3
De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy.从头设计一种雄激素受体 DNA 结合域靶向肽 PROTAC 用于前列腺癌治疗。
Adv Sci (Weinh). 2022 Oct;9(28):e2201859. doi: 10.1002/advs.202201859. Epub 2022 Aug 15.
4
Therapeutic Strategies to Target the Androgen Receptor.靶向雄激素受体的治疗策略。
J Med Chem. 2022 Jul 14;65(13):8772-8797. doi: 10.1021/acs.jmedchem.2c00716. Epub 2022 Jul 5.
5
(+)-JJ-74-138 is a Novel Noncompetitive Androgen Receptor Antagonist.(+)-JJ-74-138 是一种新型非竞争性雄激素受体拮抗剂。
Mol Cancer Ther. 2022 Apr 1;21(4):483-492. doi: 10.1158/1535-7163.MCT-21-0432.
6
Selective degradation of AR-V7 to overcome castration resistance of prostate cancer.选择性降解 AR-V7 以克服前列腺癌的去势抵抗。
Cell Death Dis. 2021 Sep 21;12(10):857. doi: 10.1038/s41419-021-04162-0.
7
Ligand Binding Prolongs Androgen Receptor Protein Half-Life by Reducing its Degradation.配体结合通过减少雄激素受体蛋白的降解来延长其半衰期。
J Endocr Soc. 2021 Mar 5;5(5):bvab035. doi: 10.1210/jendso/bvab035. eCollection 2021 May 1.
8
Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer.雄激素受体核定位在去势抵抗性前列腺癌中的调控和靶向作用。
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI141335.
9
Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy.雄激素受体剪接变体 7 和雄激素受体新型 PROTAC MTX-23 对二线抗雄激素治疗抵抗的 CRPC 的影响。
Mol Cancer Ther. 2021 Mar;20(3):490-499. doi: 10.1158/1535-7163.MCT-20-0417. Epub 2020 Dec 4.
10
Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer.前列腺癌中雄激素依赖性和非依赖性雄激素受体活性的翻译后调控
Asian J Urol. 2020 Jul;7(3):203-218. doi: 10.1016/j.ajur.2019.11.001. Epub 2019 Nov 20.
Zotero 插件