靶向蛋白质泛素修饰及降解在前列腺癌治疗中的机遇与挑战^*

Prostate cancer is the fastest growing cancer among Chinese male population. Resistance to antiandrogen therapy is the leading cause of death in patients with prostate cancer. Therefore, solving the drug resistance conundrum is the key issue for translational research in prostate cancer. Mammalian cells utilize the ubiquitin-proteasome system to degrade targeted proteins. Consequently, key oncogenes in prostate cancer, such as upstream ubiquitination regulators (e.g., deubiquitinases) of androgen receptor (AR), are potential therapeutic targets. However, these enzymes have a broad spectrum of substrates and may be off target. Recently, the proteolysis-targeting chimeras (PROTAC) technology developed based on the ubiquitin-proteasome system is the most promising and revolutionary new anti-cancer drug discovery technology, enabling the degradation of target proteins by specific E3 ubiquitin ligases without affecting other substrates. Compared with traditional small molecule inhibitors, PROTAC hold great advantages in overcoming drug resistance as well as targeting undruggable targets. Currently, the PROTAC degraders targeting the AR has achieved success in phase II clinical trials. In the future, the new technology targeting protein ubiquitination and degradation pathway will bring new breakthroughs for the clinical treatment of prostate cancer.