蛋白降解靶向嵌合体的研究进展

Research Progress on Proteolysis Targeting Chimeras

传统的小分子激酶抑制剂药物面临着诸多挑战,如易产生耐药性和部分靶点不可成药的问题。蛋白降解靶向嵌合体(PROTAC)技术利用细胞内固有的泛素-蛋白酶体系统,实现对靶蛋白(POI)的降解以治疗疾病,可避免靶点不可成药和耐药性的限制,有望克服小分子抑制剂的局限。目前多款PROTAC已进入临床试验阶段,成为许多疾病潜在的治疗方式。文章综述了PROTAC的生物学机制、技术优势、分子设计及其临床应用前景,以期为其药物开发与临床应用提供参考。

Traditional small molecule kinase inhibitor drugs face numerous challenges,such as the propensity for drug resistance and the problem that some targets are undruggable.The proteolysis targeting chimera(PROTAC)technology utilizes the inherent ubiquitin-proteasome system in cells to achieve the degradation of proteins of interest(POI)for treating diseases,which can avoid the limitations of undruggable targets and drug resistance.Therefore,the PROTAC technology is expected to overcome the limitations of small molecule inhibitors.At present,some PROTACs have entered the clinical trial stage and are expected to become potential treatment methods for many diseases.This review introduces the biological mechanism,technical advantages,molecular design and clinical application prospects of PROTAC,hoping to provide a reference for its drug development and clinical application.