PROTAC技术：机遇与挑战。

PROTAC Technology: Opportunities and Challenges.

作者信息

Gao Hongying, Sun Xiuyun, Rao Yu

机构信息

MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, P.R. China.

Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100084, P.R. China.

出版信息

ACS Med Chem Lett. 2020 Mar 12;11(3):237-240. doi: 10.1021/acsmedchemlett.9b00597.

DOI:10.1021/acsmedchemlett.9b00597

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7073876/

Abstract

PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology companies. PROTACs opened a new chapter for novel drug development. However, any new technology will face many new problems and challenges. Perspectives on the potential opportunities and challenges of PROTACs will contribute to the research and development of new protein degradation drugs and degrader tools.

摘要

PROTAC诱导的靶向蛋白降解已成为药物开发中的一种新型治疗策略，并受到学术机构、大型制药企业（如阿斯利康、拜耳、诺华、安进、辉瑞、葛兰素史克、默克和勃林格殷格翰等）以及生物技术公司的青睐。PROTAC为新型药物开发开启了新篇章。然而，任何新技术都会面临许多新问题和挑战。对PROTAC潜在机遇和挑战的展望将有助于新型蛋白降解药物和降解剂工具的研发。

相似文献

1

PROTAC Technology: Opportunities and Challenges.PROTAC技术：机遇与挑战。

ACS Med Chem Lett. 2020 Mar 12;11(3):237-240. doi: 10.1021/acsmedchemlett.9b00597.

2

Total Synthesis of Colombiasin A This work was financially supported by the National Institutes of Health (USA) and The Skaggs Institute for Chemical Biology, postdoctoral fellowships from Bayer AG (to R.K. and W.M.), and grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.哥伦比亚毒素A的全合成本研究得到了美国国立卫生研究院、斯卡格斯化学生物学研究所、拜耳公司提供的博士后奖学金（授予R.K.和W.M.）以及雅培、安进、Array生物制药、勃林格殷格翰、葛兰素史克、霍夫曼-罗氏、杜邦、默克、诺华、辉瑞和先灵葆雅等公司的资助。

Angew Chem Int Ed Engl. 2001 Jul 2;40(13):2482-2486.

3

PROTAC-DB: an online database of PROTACs.PROTAC-DB：一个 PROTAC 数据库。

Nucleic Acids Res. 2021 Jan 8;49(D1):D1381-D1387. doi: 10.1093/nar/gkaa807.

4

Targeted protein degradation by PROTACs.通过 PROTACs 进行靶向蛋白降解。

Pharmacol Ther. 2017 Jun;174:138-144. doi: 10.1016/j.pharmthera.2017.02.027. Epub 2017 Feb 14.

5

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy.蛋白水解靶向嵌合体（PROTAC）用于靶向蛋白降解和癌症治疗。

J Hematol Oncol. 2020 May 13;13(1):50. doi: 10.1186/s13045-020-00885-3.

6

Synthesis of the ABCD Ring System of Azaspiracid We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), The Skaggs Institute for Chemical Biology, a predoctoral fellowship from Bristol-Myers Squibb (to F.B.), postdoctoral fellowships from The Skaggs Institute for Research (to W.Q.), the Academy of Finland, the Ella and Georg Ehrnrooth Foundation and the Tauno Tönning Foundation (all to P.M.P.), and Bayer AG (to J.H.), as well as grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.azaspiracid的ABCD环系统的合成我们分别感谢D. H. Huang博士和G. Siuzdak博士在核磁共振光谱和质谱分析方面提供的帮助。这项工作得到了美国国立卫生研究院、斯卡格斯化学生物学研究所、百时美施贵宝公司提供的博士前奖学金（给F.B.）、斯卡格斯研究所提供的博士后奖学金（给W.Q.）、芬兰科学院、埃拉和格奥尔格·埃尔恩罗思基金会以及陶诺·滕宁基金会（均给P.M.P.）、拜耳公司（给J.H.）的资助，以及雅培、安进、ArrayBiopharma、勃林格殷格翰、葛兰素史克、霍夫曼-罗氏、杜邦、默克、诺华、辉瑞和先灵葆雅公司提供的拨款。

Angew Chem Int Ed Engl. 2001 Nov 5;40(21):4068-4071.

7

Total Synthesis of Apoptolidin: Part 1. Retrosynthetic Analysis and Construction of Building Blocks We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, American Biosciences, a pre-doctoral fellowship from Boehringer Ingelheim (Y.L.), a postdoctoral fellowship the George Hewitt Foundation (K.C.F.), and grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Schering Plough.凋亡诱导素的全合成：第1部分。逆合成分析与构建模块我们分别感谢D. H. Huang博士和G. Siuzdak博士在核磁共振光谱和质谱分析方面提供的帮助。这项工作得到了美国国立卫生研究院、斯卡格斯化学生物学研究所、美国生物科学公司的资助，勃林格殷格翰公司提供的博士前奖学金（Y.L.）、乔治·休伊特基金会提供的博士后奖学金（K.C.F.），以及雅培实验室、Array生物制药公司、拜耳公司、勃林格殷格翰公司、杜邦公司、葛兰素公司、霍夫曼 - 罗氏公司、默克公司、诺华公司、辉瑞公司和先灵葆雅公司的资助。

Angew Chem Int Ed Engl. 2001 Oct 15;40(20):3849-3854.

8

Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs.小分子 PROTACs：一种新兴且有前景的靶向治疗药物开发方法。

EBioMedicine. 2018 Oct;36:553-562. doi: 10.1016/j.ebiom.2018.09.005. Epub 2018 Sep 14.

9

Structured lifestyle education for people with schizophrenia, schizoaffective disorder and first-episode psychosis (STEPWISE): randomised controlled trial.《精神分裂症、分裂情感障碍和首发精神病患者的结构化生活方式教育（STEPWISE）：随机对照试验》

Br J Psychiatry. 2019 Feb;214(2):63-73. doi: 10.1192/bjp.2018.167. Epub 2018 Sep 25.

10

Synthesis of the FGHI Ring System of Azaspiracid We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. Financial support for this work was provided by The Skaggs Institute for Chemical Biology, the National Institutes of Health (USA), a predoctoral fellowship from Bristol-Myers Squibb (F.B.), postdoctoral fellowships from the Academy of Finland, the Ella and Georg Ehrnrooth Foundation, and the Tauno Tönning Foundation (all to P.M.P.), ArrayBiopharma (N.Z.), and Bayer AG (N.D.), and grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.azaspiracid的FGHI环系统的合成我们分别感谢D. H. Huang博士和G. Siuzdak博士在核磁共振光谱和质谱分析方面提供的帮助。这项工作得到了斯卡格斯化学生物学研究所、美国国立卫生研究院、百时美施贵宝公司提供的博士前奖学金（给F.B.）、芬兰科学院、埃拉和格奥尔格·埃尔恩罗思基金会、陶诺·滕宁基金会（均给P.M.P.）、ArrayBiopharma公司（新西兰）、拜耳公司（给N.D.）的博士后奖学金，以及雅培公司、安进公司、ArrayBiopharma公司、勃林格殷格翰公司、葛兰素公司、霍夫曼-罗氏公司、杜邦公司、默克公司、诺华公司、辉瑞公司和先灵葆雅公司提供的资助。

Angew Chem Int Ed Engl. 2001 Apr 1;40(7):1262-1265.

引用本文的文献

1

Target sequence-conditioned design of peptide binders using masked language modeling.使用掩码语言建模的肽结合物的靶序列条件设计。

Nat Biotechnol. 2025 Aug 13. doi: 10.1038/s41587-025-02761-2.

2

Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.葡萄糖代谢及其在癌症和免疫调节中的直接作用：代谢靶向的机遇与挑战

J Biomed Sci. 2025 Jul 29;32(1):71. doi: 10.1186/s12929-025-01167-1.

3

PROTAC-Based Antivirals for Respiratory Viruses: A Novel Approach for Targeted Therapy and Vaccine Development.基于PROTAC的呼吸道病毒抗病毒药物：靶向治疗和疫苗开发的新方法

Microorganisms. 2025 Jul 2;13(7):1557. doi: 10.3390/microorganisms13071557.

4

TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.TrypPROTACs：为恰加斯病解锁新的治疗策略

Pharmaceuticals (Basel). 2025 Jun 19;18(6):919. doi: 10.3390/ph18060919.

5

Methods to accelerate PROTAC drug discovery.加速PROTAC药物发现的方法。

Biochem J. 2025 Jun 25;482(13):BCJ20243018. doi: 10.1042/BCJ20243018.

6

PROTAC Technology as a New Tool for Modern Pharmacotherapy.PROTAC技术作为现代药物治疗的新工具。

Molecules. 2025 May 11;30(10):2123. doi: 10.3390/molecules30102123.

7

Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs.细胞外蛋白质的靶向降解：最新进展与降解剂设计的多样性

J Hematol Oncol. 2025 May 1;18(1):52. doi: 10.1186/s13045-025-01703-4.

8

Insights from protein frustration analysis of BRD4-cereblon degrader ternary complexes show separation of strong from weak degraders.BRD4-脑啡肽降解剂三元复合物的蛋白质错配分析见解显示了强效降解剂与弱效降解剂的区分。

RSC Med Chem. 2025 Feb 10. doi: 10.1039/d4md00962b.

9

Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.不依赖泛素的蛋白酶体降解机制及其在年龄相关性神经退行性疾病中的作用。

Front Cell Dev Biol. 2025 Feb 7;12:1531797. doi: 10.3389/fcell.2024.1531797. eCollection 2024.

10

MEGA PROTAC, MEGA DOCK-based PROTAC mediated ternary complex formation pipeline with sequential filtering and rank aggregation.基于MEGA DOCK的MEGA PROTAC介导的三元复合物形成流程，具有顺序过滤和排名聚合。

Sci Rep. 2025 Feb 14;15(1):5545. doi: 10.1038/s41598-024-83558-2.

本文引用的文献

1

Evolution of Cereblon-Mediated Protein Degradation as a Therapeutic Modality.作为一种治疗方式的 Cereblon 介导的蛋白质降解的演变

ACS Med Chem Lett. 2019 Nov 12;10(12):1592-1602. doi: 10.1021/acsmedchemlett.9b00425. eCollection 2019 Dec 12.

2

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo.一种强效且选择性的 STAT3 小分子降解剂在体内实现完全肿瘤消退。

Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002.

3

Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders.简单结构修饰将真正的 MDM2 PROTAC 降解剂转化为分子胶：PROTAC 降解剂设计中的一个警示故事。

J Med Chem. 2019 Nov 14;62(21):9471-9487. doi: 10.1021/acs.jmedchem.9b00846. Epub 2019 Oct 21.

4

Targeting IRAK4 for Degradation with PROTACs.利用PROTAC技术靶向降解白细胞介素-1受体相关激酶4（IRAK4）

ACS Med Chem Lett. 2019 Jun 14;10(7):1081-1085. doi: 10.1021/acsmedchemlett.9b00219. eCollection 2019 Jul 11.

5

Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes.由于 E3 连接酶复合物核心组件的基因组改变而导致对 BET-PROTACs（蛋白水解靶向嵌合体）的获得性耐药。

Mol Cancer Ther. 2019 Jul;18(7):1302-1311. doi: 10.1158/1535-7163.MCT-18-1129. Epub 2019 May 7.

6

Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas.PROTACs介导布鲁顿酪氨酸激酶突变体的降解用于潜在治疗依鲁替尼耐药的非霍奇金淋巴瘤

Leukemia. 2019 Aug;33(8):2105-2110. doi: 10.1038/s41375-019-0440-x. Epub 2019 Mar 11.

7

Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions.高选择性 PTK2 蛋白水解靶向嵌合体探究黏着斑激酶支架功能。

J Med Chem. 2019 Mar 14;62(5):2508-2520. doi: 10.1021/acs.jmedchem.8b01826. Epub 2019 Feb 22.

8

A chemical approach for global protein knockdown from mice to non-human primates.一种从小鼠到非人类灵长类动物进行整体蛋白质敲低的化学方法。

Cell Discov. 2019 Feb 5;5:10. doi: 10.1038/s41421-018-0079-1. eCollection 2019.

9

Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation.通过 PROTAC 介导的降解来解决 Fak 的激酶非依赖性功能。

J Am Chem Soc. 2018 Dec 12;140(49):17019-17026. doi: 10.1021/jacs.8b08008. Epub 2018 Nov 28.

10

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6.开发一种新型 B 细胞淋巴瘤 6（BCL6）PROTAC，深入了解 BCL6 的小分子靶向治疗。

ACS Chem Biol. 2018 Nov 16;13(11):3131-3141. doi: 10.1021/acschembio.8b00698. Epub 2018 Oct 17.

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍。

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

文档翻译

学术文献翻译模型，支持多种主流文档格式。