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PROTAC药物的应用与研究进展
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| 篇名： | PROTAC药物的应用与研究进展 |
| TITLE： | Applications and research advances of PROTAC drugs |
| 摘要： | 蛋白降解靶向嵌合体（PROTAC）凭借“事件驱动”的药理学模式，可介导靶蛋白经泛素‑蛋白酶体系统降解，为“不可成药”靶点与肿瘤耐药难题提供了新的解决路径。随着2026年vepdegestrant获美国FDA批准用于雌激素受体阳性晚期或转移性乳腺癌，PROTAC正式实现临床转化，目前已有多款靶向雄激素受体、布鲁顿酪氨酸激酶、表皮生长因子受体、白介素1受体相关激酶4的候选药物进入各期临床试验，覆盖肿瘤、炎症性疾病等多个治疗领域。但PROTAC仍面临显著成药瓶颈：高分子量带来理化性质缺陷，造成膜通透性与口服生物利用度不足；固有的“HOOK效应”增加了临床给药方案的制定难度；同时，E3泛素连接酶表达缺失或突变可诱发获得性耐药，且当前可利用的E3配体资源较为有限。为突破上述局限，研究者开发出可控激活修饰、适配体或抗体偶联、纳米递送、多靶点多价态设计等创新研发策略，不同技术各有优势，但同样伴随新的成药性短板，如光敏基团穿透受限、偶联分子稳定性不足、纳米制剂规模化生产困难等。人工智能辅助分子设计、拓展新型E3泛素连接酶配体、拓宽疾病适应证是未来重要发展方向，可能会为PROTAC分子优化、临床前开发与临床转化提供参考。 |
| ABSTRACT： | Proteolysis-targeting chimeras （PROTACs）， with their “event-driven” pharmacological mode， can mediate the degradation of target proteins through the ubiquitin-proteasome system， providing a new solution to the challenges of “undruggable” targets and tumor drug resistance. With the approval of vepdegestrant by U.S. FDA in 2026 for estrogen receptor-positive advanced or metastatic breast cancer， PROTACs have officially achieved clinical translation. Currently， multiple candidate drugs targeting androgen receptor， Bruton’s tyrosine kinase， epidermal growth factor receptor and interleukin-1 receptor-associated kinase 4 have entered various phases of clinical trials， covering multiple therapeutic fields such as tumors and inflammatory diseases. However， PROTACs still face significant drug development bottlenecks： their high molecular weight leads to defects in physicochemical properties， resulting in insufficient membrane permeability and oral bioavailability； the inherent “HOOK effect” increases the difficulty of formulating clinical dosing regimens； meanwhile， loss or mutation of E3 ubiquitin ligase expression can induce acquired drug resistance， and the currently available E3 ligand resources are relatively limited. To overcome these limitations， innovative research and development strategies such as controllable activation modification， aptamer or antibody conjugation， nanodelivery and multi-target multivalent design have been developed. Different technologies have their own advantages， but they are also accompanied by new drug development shortcomings， such as limited penetration of photosensitive groups， insufficient stability of conjugated molecules and difficulties in large-scale production of nanoformulations. Artificial intelligence-assisted molecular design， expansion of novel E3 ubiquitin ligase ligands and broadening of disease indications are important future development directions， which may provide references for the molecular optimization， preclinical development and clinical translation of PROTACs. |
| 期刊： | 2026年第37卷第18期 |
| 作者： | 潘昭平；何谷；吴逢波 |
| AUTHORS： | PAN Zhaoping，HE Gu，WU Fengbo |
| 关键字： | 蛋白降解靶向嵌合体;vepdegestrant;临床转化;创新策略 |
| KEYWORDS： | PROTACs;vepdegestrant;clinical translation;innovative strategies |
| 阅读数： | 6 次 |
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