Wang Ling-Yu, Hung Chiu-Lien, Wang Tsan-Chun, Hsu Hung-Chih, Kung Hsing-Jien, Lin Kwang-Huei
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
Annu Rev Pharmacol Toxicol. 2025 Jan;65(1):375-396. doi: 10.1146/annurev-pharmtox-030624-110238. Epub 2024 Dec 17.
Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.
去势抵抗性前列腺癌(CRPC)由于对传统的雄激素受体(AR)靶向治疗具有抗性,在临床管理中面临重大挑战。蛋白水解靶向嵌合体(PROTACs)的出现彻底改变了癌症治疗方式,通过实现对参与CRPC进展的关键分子的靶向降解。在本综述中,我们讨论了用于CRPC治疗的PROTACs的发展,重点关注AR和其他与CRPC相关的调节因子。我们从靶向位点选择和临床前抗肿瘤评估方面概述了AR PROTAC开发的战略趋势,以及临床应用中AR降解剂的最新情况。此外,我们简要介绍了选择性AR降解剂的开发现状。此外,我们回顾了PROTACs作为潜在CRPC治疗范例的新进展,重点介绍了那些靶向染色质调节剂BRD4、EZH2和SWI/SNF;转录调节因子SMAD3;以及激酶CDK9和PIM1的研究。鉴于CRPC和神经内分泌前列腺癌(NEPC)之间共享分子靶点,我们还讨论了PROTACs在治疗NEPC方面的潜力。