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.
诱导蛋白质降解已成为一种创新的药物发现方法，与抑制蛋白质功能的经典方法形成互补。雄激素受体信号通路已被确定为致命性去势抵抗性前列腺癌发生和发展的主要驱动力。由于雄激素受体降解剂的作用机制不同于雄激素受体拮抗剂，它们有望克服当前疗法面临的耐药性挑战。蛋白水解靶向嵌合体、单体降解剂、疏水标记、分子胶以及自噬降解等方法均已证明能够下调细胞内雄激素受体浓度。六种蛋白水解靶向嵌合体和两种单体雄激素受体降解剂已进入I期或II期临床试验，这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。尽管已有研究综述了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，但随着新型雄激素受体降解剂和新策略的不断涌现，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范式的最新进展，概述了自2020年以来取得的进展。
Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer
肿瘤(癌症)患者之家