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| 1 | Developing potent PROTACs tools for selective degradation of HDAC6 protein显示文摘Dear Editor, Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups on histone and non-histone proteins, thereby playing a vital role in the modulation of gene expression and protein activity. Eighteen HDACs have been identified in human and subdivided into four classes including I, II (Ila, lib), III and IV (Seto et al., 2014). Among them, HDAC6 is a unique lib HD AC with dominant cytoplasmic localization and two functional catalytic domains. Besides the functions for deacetylation of histone, and modulation of a-tubulin, HSP90 and cortactin, HDAC6 also participates in protein trafficking and degradation, cell shape and migration (Valenzuela-Fernandez et al., 2008). The deregulation of HDAC6 is related to various diseases, such as neurodegenerative diseases, cancer and pathological autoimmune response (Batchu et al., 2016). Hence, it is especially important for directly controlling cellular HDAC6 protein levels to achieve therapeutic purposes. The traditional approaches of red u ci ng cellular protein levels mainly rely on genetic modifications, such as RNA interference, transcription activator-like effector nucleases, recombination-based gene knockout and clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)(Boettcher et al., 2015). However, these approaches have failed to a certain degree to achieve acute and reversible changes of gene function. Furthermore, the complications of potential genetic compensation and/or spontaneous mutations arising in geneknockout models may lead to misinterpretations (Davisson etal., 2012;El-Brolosy etal., 2017). Therefore, it is urgent for developing a rapid, robust, and reversible approach to directly modulate HDAC6 protein levels. | Zixuan An Wenxing Lv Shang Su Wei Wu Yu Rao | 2019 | Protein & Cell2019，10，8： | 7 |
| 2 | 布鲁顿酪氨酸激酶靶向药物的研究进展显示文摘布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase,BTK)是B细胞抗原受体信号转导通路中的关键激酶,参与B细胞增殖、分化和凋亡的调节,同时在多种信号通路的调控及肿瘤和炎症的发生和发展中也起着重要作用,已成为治疗恶性血液病和自身免疫性疾病的重要靶点。目前已上市的BTK靶向药物依鲁替尼、阿卡替尼和泽布替尼,对B细胞恶性肿瘤显示出较好的临床疗效,此外已有多个药物进入临床研究,表现出较好的开发前景。靶向BTK的靶向蛋白降解嵌合体分子的发展,有望解决依鲁替尼引起的耐药,更好地推动BTK靶向药物的研发。本文主要对BTK靶向药物的研究进展进行综述,为合理开发BTK靶向药物提供启示。 | 王姝 黄文海 沈正荣 | 2020 | 中国现代应用药学2020，37，24： | 6 |
| 3 | 靶向蛋白质降解技术研究进展显示文摘靶向蛋白质降解技术可有效克服DNA敲除、RNA干扰等传统药物靶点确认及干扰策略的局限性。近年来,一系列新型靶向蛋白质降解技术不断涌现,在药物研发领域展现出极好的应用前景。本文综述了靶向蛋白质降解技术的最新研究进展,重点介绍各种技术的作用机制、应用情况、技术优势及目前存在问题,以期为药物靶点确认及新药开发提供有力理论及技术支持。 | 张晓元 张艳艳 孙晓康 张林军 陈勉 刘飞 | 2022 | 生物化学与生物物理进展2022，49，1： | 6 |
| 4 | 小分子蛋白降解靶向嵌合体的研究进展显示文摘蛋白降解靶向嵌合体(proteolytic targeting chimera,PROTAC)是一种通过泛素-蛋白酶体系统选择性降解靶蛋白的新技术。PROTAC是一类异双功能分子,其中包含靶向目标蛋白质的配体,募集E3连接酶的配体和连接这2个配体的接头。与传统抑制剂相比,它们在功效、选择性和耐药性方面均具有许多优势。因此,近二十年来已经开发了许多有前途的PROTACs,尤其是小分子PROTACs。本文选择CRBN、VHL、MDM2和cIAP14种常见E3连接酶为代表,针对不同的靶向目标进行分类,在阐述4种E3连接酶各自特点的同时,也综述了基于不同E3连接酶的小分子PROTACs的研究进展。 | 谢妙红 高明明 凌佳楠 杜文婷 | 2021 | 中国现代应用药学2021，38，22： | 5 |
| 5 | 蛋白质降解靶向嵌合体的研究进展显示文摘近年来,蛋白质降解靶向嵌合体(proteolysis targeting chimeras,PROTACs)作为一种新型靶向治疗方式成为人们关注的焦点。PROTACs是一类双靶点嵌合体分子,由3个部分组成:靶向结合目标蛋白的配体、招募E3泛素连接酶的配体以及两者之间的连接链。它能将目标蛋白与E3泛素连接酶的距离拉近,利用细胞内固有的泛素-蛋白酶体系统选择性诱导目标蛋白降解。与传统的小分子抑制剂相比,PROTACs在药物的剂量、选择性、耐药性以及调节“不可成药靶点”等方面具有潜在优势,目前已开始从基础研究走向临床试验。笔者将结合最新的相关研究进展,总结PROTACs的优势、设计要素以及目前面临的主要问题等。 | 余赛红 王孝举 郑晓亮 于洁 | 2021 | 中国药学杂志2021，56，11： | 4 |
| 6 | 蛋白水解靶向嵌合分子的小分子抗肿瘤药物的研究进展显示文摘近年来蛋白靶向降解(PROTAC)技术作为一种新的治疗手段在抗肿瘤药物领域中得到了广泛的研究。PROTAC是一种双功能的小分子化合物,可以将靶蛋白与E3泛素连接酶连接形成三元复合物,通过泛素–蛋白酶体系降解靶蛋白。雌激素(ER)、雄激素(AR)、间变性淋巴瘤激酶(ALK)、布鲁顿酪氨酸激酶(BTK)、溴结构域蛋白4(BRD4)和细胞周期蛋白依赖激酶8(CDK8)等多种蛋白已经被选为靶蛋白进行了研究。对PROTAC的小分子抗肿瘤药物的研究进展进行综述。 | 崔洁 魏会强 宁洪鑫 李祎亮 | 2019 | 现代药物与临床2019，34，10： | 3 |
| 7 | PROTACs: great opportunities for academia and industry显示文摘Although many kinds of therapies are applied in the clinic,drug-resistance is a major and unavoidable problem.Another disturbing statistic is the limited number of drug targets,which are presently only 20–25%of all protein targets that are currently being studied.Moreover,the focus of current explorations of targets are their enzymatic functions,which ignores the functions from their scaffold moiety.As a promising and appealing technology,PROteolysis TArgeting Chimeras(PROTACs)have attracted great attention both from academia and industry for finding available approaches to solve the above problems.PROTACs regulate protein function by degrading target proteins instead of inhibiting them,providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions.PROTACs have been proven to show better selectivity compared to classic inhibitors.PROTACs can be described as a chemical knockdown approach with rapidity and reversibility,which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations.PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases,but also in immune disorders,viral infections and neurodegenerative diseases.Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology,more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic.More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration. | Xiuyun Sun Hongying Gao Yiqing Yang Ming He Yue Wu Yugang Song Yan Tong Yu Rao | 2019 | Signal Transduction and Targeted Therapy2019，4，1： | 3 |
| 8 | 蛋白降解靶向嵌合体在小分子药物研发中的机遇与挑战显示文摘蛋白降解靶向嵌合体(PROTAC)技术是一种通过泛素-蛋白酶体途径化学诱导靶蛋白降解的新兴策略。PROTAC是由靶蛋白配体和E3泛素连接酶配体通过适当的连接链连接而成的双功能分子,能够同时招募靶蛋白和E3泛素连接酶,从而诱导靶蛋白泛素化降解,具有广泛的应用前景和发展空间。主要简述小分子PROTAC的降解机制、发展历程,以及在药物研发中面临的机遇与挑战。 | 曾申昕 黄文海 沈正荣 | 2020 | 药学进展2020，44，11： | 2 |
| 9 | 药物化学视角的新药创制显示文摘以患者需求为核心,实现临床价值为导向,是新药创制的宗旨和路径。无论首创性药物或是仿创性药物都是为了满足患者对无药可治或更加安全有效的药物需求。以生物学基础研究驱动的创新药物,为实现临床价值包含三个要素或环节,即理解致病的分子机制;把握疾病的微观特征;阐明药物的作用机制。这三者之间的相互关联,是贯穿其中的转化医学,药物化学扮演重要角色。即将生物学/医学的基础研究成果通过各种模型阐明疾病发生发展的分子机制,从分析分子调控过程中找到治疗疾病的关键节点。患者的症状、生化常规和影像特征等宏观表象,难以在分子水平上为药物分子设计提供信息,生物学的发展,得以在微观水平作分子生物学分析,例如基因缺失与变异、蛋白质组学、表观遗传学等技术,结合疾病的分子机制,可从多样本和大数据分析中归纳基因-蛋白(酶、受体、通道、信号分子等)与疾病的关系,对创制新药和疗法提供新的科学依据。洞察疾病的微观特征是上述发病的分子机制的延续和深化,为创制新药提供可行的科学路径。当阐明了疾病的分子机制和药物的作用机制,对既有药物(或活性物质)的应用就有了更深刻和广泛的认识,提供了药物设计和应用的新思路。构建新分子结构(NME)的药物化学是其中的重要环节,要求药物化学研究者扩展固有的靶标-设计-合成-评价的模式,从大视野的角度,上溯关注基础研究及其成果,及时向创制新药的方向转轨;向下游关注临床要求,结合疾病的微观特征,落实转化过程的具体内容,这对于首创性药物的研发是非常关键的步骤。本文从药物化学视角浅谈一些看法。 | 郭宗儒 | 2022 | 药学学报2022，57，2： | 1 |
| 10 | 靶向蛋白降解技术及其在疾病治疗中的研究进展显示文摘靶向蛋白降解(Targeted protein degradation,TPD)技术利用细胞内天然存在的两大蛋白降解系统:泛素化-蛋白酶体系统与溶酶体降解途径实现对疾病相关蛋白的特异、高效降解,从而达到疾病治疗的效果。相较于传统的小分子抑制剂,基于TPD技术的药物在靶点蛋白的选择上限制性更小,能够作用于'无成药性'的蛋白,从而拥有更为丰富的靶点库。与在基因、m RNA层面干扰蛋白表达的技术相比,TPD药物具有特异、快速以及不受蛋白翻译后修饰约束等特点。在过去的20年里,基于TPD技术的各类降解系统层出不穷,相关研究成果在近些年呈爆发式增长,更令人兴奋的是,2019年两种基于TPD技术的治疗性药物进入临床阶段并初步显示出良好的治疗效果。虽然TPD技术的发展处于起步阶段,目前仍存在诸多缺陷,但凭借其独有的优势,在不久的将来,该技术必将成为药物研发的主要手段之一,同时,也将给学术界和产业界带来前所未有的机遇。本综述详细介绍了基于TPD技术的不同降解系统的研究现状,阐述了各系统在疾病治疗中的应用,系统地总结了各自的优势和不足,以期为TPD技术在科学研究和药物研发中的进一步应用提供理论指导。 | 陈淑萍 杨晗 蒋金露 于思远 李廷栋 葛胜祥 | 2021 | 生物工程学报2021，37，11： | 1 |
| 11 | PROTACs在肿瘤治疗领域的研究与应用显示文摘蛋白水解靶向嵌合分子(protein proteolysis-targeting chimeras,PROTACs)是一种可以直接降解靶蛋白的双功能嵌合体。PROTACs通过中间连接链将靶蛋白与E3泛素连接酶结合的配体连接起来,继而泛素化修饰靶蛋白,从而使其进入蛋白酶体途径降解。根据PROTACs的作用机理,可以设计合成靶向降解调控肿瘤发生发展相关蛋白的PROTAC分子,从而达到治疗肿瘤的效果。目前,多个靶向肿瘤相关蛋白(BET蛋白、TBK1、CDK4/6以及AR、ER等)的PROTAC分子已在体外和体内实验中表现出良好的作用效果,有望研究开发成为肿瘤靶向药物。本文将对PROTACs的发展及其在肿瘤治疗领域的应用进行述评。 | 韩苏夏 孙潇 蔡梦娇 | 2019 | 西部医学2019，31，9： | 1 |
| 12 | Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets显示文摘Cancer immunotherapy harness the body's immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic targets.Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole cells.Targeted protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target proteins.The recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer targets.Further studies on these molecules'modes of action,target-binding'warheads',lysosomal sorting signals,and linker design should facilitate their rational design.Modifications and derivatives may improve their cell-penetrating ability and thein vivo stability of these pro-drugs.These studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor growth.Here,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed. | Yungang Wang Shouyan Deng Jie Xu | 2020 | Cancer Biology & Medicine2020，17，3： | 1 |
| 13 | Proteolysis targeting chimera technology:a novel strategy for treating diseases of the central nervous system显示文摘Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are lacking.Proteolysis targeting chimera(PROTAC)technology is a novel strategy to solve this problem.PROTAC technology uses the ubiquitin-protease system to eliminate mutated,denatured,and harmful proteins in cells.It can be reused,and utilizes the protein destruction mechanism of the cells,thus making up for the deficiencies of traditional protein degradation methods.It can effectively target and degrade proteins,including proteins that are difficult to identify and bind.Therefore,it has extremely important implications for drug development and the treatment of neurological diseases.At present,the targeted degradation of mutant BTK,mHTT,Tau,EGFR,and other proteins using PROTAC technology is gaining attention.It is expected that corresponding treatment of nervous system diseases can be achieved.This review first focuses on the recent developments in PROTAC technology in terms of protein degradation,drug production,and treatment of central nervous system diseases,and then discusses its limitations.This review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases. | Ke Ma Xiao-Xiao Han Xiao-Ming Yang Song-Lin Zhou | 2021 | Neural Regeneration Research2021，16，10： | 1 |
| 14 | PROTACs:great opportunities for academia and industry (an update from 2020 to 2021)显示文摘PROteolysis TArgeting Chimeras(PROTACs)technology is a new protein-degradation strategy that has emerged in recent years.It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system.PROTACs can not only be used as potential clinical treatments for diseases such as cancer,immune disorders,viral infections,and neurodegenerative diseases,but also provide unique chemical knockdown tools for biological research in a catalytic,reversible,and rapid manner.In 2019,our group published a review article“PROTACs:great opportunities for academia and industry”in the journal,summarizing the representative compounds of PROTACs reported before the end of 2019.In the past 2 years,the entire field of protein degradation has experienced rapid development,including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage.In addition to PROTAC and molecular glue technology,other new degradation technologies are also developing rapidly.In this article,we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation.The problems that need to be solved in this field will also be briefly introduced. | Ming He Chaoguo Cao Zhihao Ni Yongbo Liu Peilu Song Shuang Hao Yuna He Xiuyun Sun Yu Rao | 2022 | Signal Transduction and Targeted Therapy2022，7，7： | 1 |
| 15 | 布鲁顿酪氨酸激酶抑制剂在淋巴瘤中的研究进展显示文摘B细胞受体(B cell receptor,BCR)信号通路的慢性持续性激活在B细胞血液系统疾病的发生发展中发挥关键作用。布鲁顿酪氨酸激酶(Burton's tyrosine kinase,BTK)是该信号通路中的一个重要激酶。通过靶向BTK而调控BCR信号通路的传导,已成为治疗多种B细胞淋巴瘤的新方向。第一代BTK抑制剂——伊布替尼在治疗B细胞恶性肿瘤中取得了突破性进展,但仍有部分患者出现原发或继发耐药。此外,由于脱靶效应,不良反应也较为明显。因此,近年来新型BTK抑制剂的研发及其与其他药物的联合治疗引起了研究者们的关注。本文就BTK抑制剂在B细胞淋巴瘤治疗中相关的临床研究进展进行综述。 | 于慧 邓丽娟 朱军 | 2020 | 肿瘤综合治疗电子杂志2020，6，2： | 1 |
| 16 | 基于多特异性结合策略的抗病毒药物研究进展显示文摘为应对病毒耐药株的不断涌现和新型病毒感染性疾病的暴发,基于新策略的抗病毒药物研发成为重要且紧迫的研究课题。近年来,快速发展的多特异性结合策略已成为研究的焦点,并在抗病毒领域得到了广泛应用。本文从药物化学角度综述了多特异性结合策略在抗病毒领域的前沿进展,并对其面临的挑战及未来前景进行了讨论。 | 周洋 徐淑静 丁当 王硕 刘新泳 展鹏 | 2023 | 药学学报2023，58，8： | 1 |
| 17 | 蛋白水解靶向嵌合体应用于恶性肿瘤治疗的实验研究进展显示文摘蛋白水解靶向嵌合体(PROTAC)是一种靶向蛋白降解技术,可将许多“不可成药”的疾病相关蛋白作为靶点,具有良好的靶向性和高效的降解性,在恶性肿瘤治疗领域显示出较好的前景。PROTAC包含三个部分,两端分别是E3泛素连接酶招募元件和靶蛋白结合配体,中间由一个连接两端配体的连接体组成,通过劫持E3泛素连接酶活性将靶蛋白泛素化降解。近年来PROTAC已从第一代肽基PROTAC发展到靶向激素受体、溴结构域和超末端结构域(BET)蛋白家族、蛋白激酶等的第二代小分子基PROTAC,为靶向治疗恶性肿瘤提供可能。目前已有两种PROTAC药物通过Ⅰ期临床试验。第三代光控式PROTAC解决了非肿瘤特异性的难题,降低了毒性,在未来可被应用于局部疾病的治疗。 | 占莹 王涛 柳长柏 | 2022 | 中国新药与临床杂志2022，41，7： | 1 |
| 18 | Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo显示文摘HMG-CoA reductase(HMGCR) protein is usually upregulated after statin(HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera(PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC(21 c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells(DC50 Z 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21 b reveled favorable plasma exposures referring to both the parent 21 b and the conversed acid 21 c. Further in vivo studies of 21 b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases. | Guoshun Luo Zhenbang Li Xin Lin Xinyu Li Yu Chen Kun Xi Maoxu Xiao Hanlin Wei Lizhe Zhu Hua Xiang | 2021 | Acta Pharmaceutica Sinica B2021，11，5： | 1 |
| 19 | 例解生物学驱动的药物设计显示文摘药理活性和成药性原则上取决于药物的微观结构和宏观性质,这些都寓于分子结构之中。药物化学将活性化合物演化成药物,是将二者融合一起,优化而得。融合操作既可以是内在的结构体现,也可以是外在的片段连接。新世纪以来的生物学进展为此提供了许多切入点,例如人源化单克隆抗体、蛋白酶体-泛素系统、变构调节、天然大环化合物、结构生物学等。本文以上市的或处于临床试验的药物研发要点,尝试解析生物学驱动的研发理念。 | 郭宗儒 | 2020 | 药学学报2020，55，8： | 1 |
| 20 | BTK抑制剂耐药机制及应对策略显示文摘恶性B细胞淋巴瘤中常见B细胞受体(B cell receptor,BCR)信号通路异常激活,布鲁顿酪氨酸激酶(Bruton's tyrosine kinase,BTK)是BCR通路的关键酶,对恶性B细胞增殖分化起着关键作用,也是淋巴瘤重要的治疗靶点。近年来BTK抑制剂陆续进入临床应用,并取得了良好的效果,为患者带来了转机。但是,越来越多的研究显示随着药物的使用,部分患者出现了对BTK抑制剂的原发或继发耐药,因此解决耐药问题也成为新的研究热点。本文就BTK抑制剂的应用现状、耐药机制及其应对策略进行综述。 | 刘康 王亮 | 2022 | 中国癌症防治杂志2022，14，1： | 0 |
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