雄激素受体降解剂的研究进展

Research Progress of Androgen Receptor Degraders

由于雄激素受体配体结合域的点突变、表达剪切变异体等诸多因素,使得现有的前列腺癌治疗手段相继无效,因此亟需新的策略用于前列腺癌的治疗。近年来靶向蛋白降解技术取得巨大进展,其中雄激素受体降解剂通过促进雄激素受体的降解来阻断雄激素受体信号通路,有望解决临床前列腺癌患者出现耐药的问题。该综述围绕靶向雄激素受体的蛋白降解靶向嵌合体(PROTAC)技术和小分子降解剂,分别从作用机制和代表性化合物两方面概述了该领域的研究进展。相较于PROTAC分子固有的成药性缺陷,小分子雄激素受体降解剂更具优势,现正成为治疗前列腺癌的主要研究方向。

Due to many factors,such as point mutations in the ligand-binding domain of the androgen receptor(AR)and expression of splice variants,the existing treatment methods for prostate cancer have been successively ineffective.Therefore,new strategies for prostate cancer treatment are urgently needed.In recent years,significant progress has been made in targeted protein degradation technology.For example,AR degraders,which are expected to solve the problem of drug resistance in clinical prostate cancer patients,can block the androgen receptor signaling pathway by promoting AR degradation.This review focuses on the proteolysis targeting chimeras(PROTAC)technology and small molecule degraders targeting AR,and summarizes the research progress in this field from the mechanism of action and representative compounds,respectively.Compared with the inherent druggability defects of PROTAC molecules,small molecule AR degraders have more advantages and are now becoming the leading research direction for the treatment of prostate cancer.