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去势抵抗性前列腺癌中雄激素受体降解的最新进展洞察

Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer.

作者信息

Chen Qiao-Hong, Munoz Erick, Ashong Dennis

机构信息

Department of Chemistry and Biochemistry, California State University, Fresno, CA 93740, USA.

出版信息

Cancers (Basel). 2024 Feb 4;16(3):663. doi: 10.3390/cancers16030663.

Abstract

Induced protein degradation has emerged as an innovative drug discovery approach, complementary to the classical method of suppressing protein function. The androgen receptor signaling pathway has been identified as the primary driving force in the development and progression of lethal castration-resistant prostate cancer. Since androgen receptor degraders function differently from androgen receptor antagonists, they hold the promise to overcome the drug resistance challenges faced by current therapeutics. Proteolysis-targeting chimeras (PROTACs), monomeric degraders, hydrophobic tagging, molecular glues, and autophagic degradation have demonstrated their capability in downregulating intracellular androgen receptor concentrations. The potential of these androgen receptor degraders to treat castration-resistant prostate cancer is substantiated by the advancement of six PROTACs and two monomeric androgen receptor degraders into phase I or II clinical trials. Although the chemical structures, in vitro and in vivo data, and degradation mechanisms of androgen receptor degraders have been reviewed, it is crucial to stay updated on recent advances in this field as novel androgen receptor degraders and new strategies continue to emerge. This review thus provides insight into recent advancements in this paradigm, offering an overview of the progress made since 2020.

摘要

诱导蛋白降解已成为一种创新的药物发现方法,是对抑制蛋白功能的经典方法的补充。雄激素受体信号通路已被确定为致死性去势抵抗性前列腺癌发生和进展的主要驱动力。由于雄激素受体降解剂的作用方式与雄激素受体拮抗剂不同,它们有望克服当前疗法所面临的耐药性挑战。蛋白酶靶向嵌合体(PROTACs)、单体降解剂、疏水标签、分子胶和自噬降解已证明它们在下调细胞内雄激素受体浓度方面的能力。六种PROTACs和两种单体雄激素受体降解剂进入I期或II期临床试验,证实了这些雄激素受体降解剂治疗去势抵抗性前列腺癌的潜力。尽管雄激素受体降解剂的化学结构、体外和体内数据以及降解机制已有综述,但随着新型雄激素受体降解剂和新策略不断涌现,及时了解该领域的最新进展至关重要。因此,本综述深入探讨了这一模式的最新进展,概述了自2020年以来所取得的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a387/10854644/45fe611785a9/cancers-16-00663-g001.jpg

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