基于PROTAC技术的靶向CDK9小分子降解剂的研究进展  

Recent progress of targeted small molecular CDK9 degraders based on PROTAC technology

作　　者：李金秀 董何伟 侯卫 LI Jin-xiu;DONG He-wei;HOU Wei(College of Pharmaceutical Science,Zhejiang University of Technology,Hangzhou 310014,China)

机构地区：[1]浙江工业大学药学院,浙江杭州310014

出　　处：《药学学报》2022年第9期2696-2708,共13页Acta Pharmaceutica Sinica

基　　金：浙江省自然科学基金资助项目(LY22H300001).

摘　　要：CDKs蛋白是一种细胞周期蛋白依赖性激酶,它们在控制细胞分裂及转录阶段发挥着重要的作用。其中,CDK9作为一种负责细胞转录延伸阶段的关键调控因子,驱动着各种恶性肿瘤细胞的发生,被认为是抗肿瘤药物研发领域的重要靶标。然而,由于CDK家族蛋白结构的高度保守性及相似性,导致传统小分子CDK9抑制剂的选择性较差,存在严重的不良反应而限制了其临床应用。鉴于此,当前迫切需要一种全新策略来研究CDK9靶点。蛋白降解靶向嵌合体(PROTAC)技术是一种新兴的药物研发策略,通过靶蛋白与泛素连接酶的间接性链接,特异性地识别靶蛋白并通过降解系统来消除目标蛋白。本文对CDK9蛋白的结构功能、与临床疾病预后不良产生的关系及明星小分子抑制剂进行简要概述,重点讨论了近几年基于PROTAC技术靶向降解CDK9蛋白的最新研究进展,并对该靶点蛋白在这一新型技术领域内的发展前景进行了总结和展望,旨在为该方向的抗肿瘤药物研发提供参考。CDKs proteins are a kind of cell cycle protein-dependent kinases,which serve as important roles in controlling cell division and transcriptional stages.Among them,CDK9,as a key regulator responsible for the transcriptional elongation of cells,drives the development of various malignant cells and is considered as an important target in the field of anti-tumor drug development.However,the CDK family proteins feature high conservativeness and similarity in structure,leading to the poor selectivity and severe side effects for traditional small-molecular CDK9 inhibitors,which has limited their clinical applications.In view of this,there is an urgent need to investigate CDK9 targets through a novel strategy.The PROTAC is an emerging drug discovery strategy that the degrader could specifically recognize the target protein through indirect linkage with ubiquitin ligases and ultimately eliminate the target protein through the ubiquitination degradation system.This paper provides a brief overview of the structure and function of CDK9 protein,its relationship with the poor prognosis of clinical diseases,as well as the currently reported small molecular inhibitors.The latest research progress on the targeted degradation of CDK9 protein based on PROTAC technology is highlighted.Finally,the development prospects of this target protein in this novel technology field are summarized and prospected,aiming to provide a reference for the development of antitumor drugs in this direction.

关 键 词：细胞周期蛋白依赖性激酶9 蛋白降解靶向嵌合体 抑制剂 抗肿瘤 降解剂 

分 类 号：R914[医药卫生—药物化学]