分子胶介导的靶向蛋白降解：从作用机制到在前列腺癌治疗中的应用前景

Molecular Glue-Mediated Targeted Protein Degradation: Mechanisms and Therapeutic Potential in Prostate Cancer

摘要: 前列腺癌(Prostate Cancer, PCa)是男性泌尿生殖系统中发病率最高的恶性肿瘤之一，其发生发展高度依赖雄激素受体(Androgen Receptor, AR)信号通路。尽管雄激素剥夺治疗及第二代AR拮抗剂在临床上取得了一定疗效，但患者往往在治疗后进展为去势抵抗性前列腺癌(Castration-Resistant Prostate Cancer, CRPC)。AR基因扩增、点突变以及剪接变体(如AR-V7)的产生，使传统以配体结合结构域(LBD)为靶点的竞争性抑制策略逐渐失效，耐药问题日益突出。因此，开发能够直接降低AR蛋白水平的全新治疗策略具有重要意义。靶向蛋白降解(Targeted Protein Degradation, TPD)技术为解决上述问题提供了新的思路。其中，分子胶(Molecular Glues, MGs)通过重编程E3泛素连接酶与底物蛋白之间的相互作用，诱导形成新的蛋白–蛋白相互作用界面，从而实现靶蛋白的选择性泛素化及蛋白酶体降解。相比于双功能PROTAC分子，分子胶具有结构更简洁、分子量较小、药代动力学性质更优等优势，在靶向“难成药”蛋白方面展现出重要的研究价值与应用潜力。

Abstract: Prostate cancer (PCa) is one of the most prevalent malignancies in the male genitourinary system, and its progression is primarily driven by the androgen receptor (AR) signaling pathway. Although androgen deprivation therapy (ADT) and second-generation AR antagonists have shown clinical efficacy, most patients eventually develop castration-resistant prostate cancer (CRPC). The emergence of AR gene amplification, point mutations, and splice variants (AR-V7) significantly diminishes the effectiveness of conventional therapies targeting the ligand-binding domain (LBD), leading to drug resistance. Therefore, the development of novel therapeutic strategies capable of directly reducing AR protein levels is of great significance. Targeted protein degradation (TPD) has emerged as a promising approach to overcome these limitations. Among TPD strategies, molecular glues (MGs) function by reprogramming the interaction between E3 ubiquitin ligases and substrate proteins, thereby inducing the formation of neomorphic protein-protein interaction interfaces and promoting ubiquitination and proteasomal degradation of target proteins. Compared with bifunctional PROTACs, molecular glues generally exhibit lower molecular weight, simpler structures, and improved pharmacokinetic properties, making them attractive candidates for targeting “undruggable” proteins.