摘要
刺激响应型蛋白质降解靶向嵌合体(PROTAC)前药可在特定刺激条件下激活PROTAC分子,实现特定区域和细胞的靶蛋白降解,从而克服不可控蛋白降解导致的毒副作用,是改善PROTAC疗效和成药性的有效策略.本文系统总结了目前用于特异性降解病灶组织目标蛋白从而精准治疗肿瘤的各种刺激响应型PROTAC前药策略.首先,本文介绍了PROTAC的发展历程和作用原理,以及目前进入临床试验阶段的PROTAC分子;然后,介绍了细胞内原位生成PROTAC的前药策略,以及各种刺激手段激活的PROTAC前药,包括外源性的光、X-射线以及内源性的肿瘤微环境的乏氧、活性氧和酶等;接着,概括了配体修饰型的主动靶向PROTAC前药,包括抗体、叶酸、适配体等修饰策略.本文重点强调了基于纳米递药系统的PROTAC前药策略,其可实现特异性肿瘤组织药物递送和精准蛋白降解.最后,本文对PROTAC的未来发展进行了探讨和展望.
The proteolysis targeting chimeras(PROTACs)approach has attracted extensive attention in the past decade,which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors.PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest(POI)via ubiquitin–proteasome system in a cycle-catalytic manner.The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable,which enormously extends the space of drug development.Furthermore,PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI.Nevertheless,PROTACs display high-efficiency and always-on properties to degrade POI,they may cause severe side effects due to an“on-target but off-tissue”protein degradation profile at the undesirable tissues and cells.Given that,the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets,which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation.Herein,we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs.We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells.
作者
高晶
杨镭
雷书敏
周峰
聂辉军
彭浡
徐田锋
陈小华
杨小宝
盛春泉
饶燏
蒲侃义
金坚
徐志爱
于海军
Jing Gao;Lei Yang;Shumin Lei;Feng Zhou;Huijun Nie;Bo Peng;Tianfeng Xu;Xiaohua Chen;Xiaobao Yang;Chunquan Sheng;Yu Rao;Kanyi Pu;Jian Jin;Zhiai Xu;Haijun Yu(Center of Pharmaceutics,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Center of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Information Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;Gluetacs Therapeutics(Shanghai)Co.,Ltd.Shanghai 201306,China;School of Pharmacy,Second Military Medical University,Shanghai 200433,China;School of Pharmaceutical Sciences,Tsinghua University,Beijing 100084,China;School of Chemical and Biomedical Engineering,Nanyang Technological University,Singapore 639798,Singapore;Mount Sinai Center for Therapeutics Discovery,Departments of Pharmacological Sciences,Oncological Sciences and Neuroscience,Tisch Cancer Institute,Icahn School of Medicine at Mount Sinai,New York NY 10029,USA;School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200241,China)
基金
supported by the National Natural Science Foundation of China(U22A20328 and 22074043)
Science and Technology Commission of Shanghai Municipality(20430711800 and23ZR1475000)
Lingang Laboratory(LG-QS-202206-04)。
