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炎症介导和自身免疫靶点中PROTACs开发的最新见解:一项批判性综述。

Recent insights of PROTAC developments in inflammation-mediated and autoimmune targets: a critical review.

作者信息

Galla Mary Sravani, Sharma Nitika, Mishra Priyanka, Shankaraiah Nagula

机构信息

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad 500037 India

出版信息

RSC Med Chem. 2024 May 8;15(8):2585-2600. doi: 10.1039/d4md00142g. eCollection 2024 Aug 14.

Abstract

According to the mounting evidence in the literature, pro-inflammatory mediators/targets activate multiple signalling pathways to trigger illnesses that are ultimately responsible for acute pain, chronic inflammatory diseases, and several auto-immune disorders. Conventional drugs have been ruled out since proteolysis-targeting chimeras (PROTACs) are poised to overcome the limitations of traditional therapies. These heterobifunctional molecules help to degrade the targeted proteins of interest through ubiquitination. This review encompasses current and future aspects of PROTACs in inflammation-mediated and autoimmune targets. Different key points are highlighted and discussed, such as why PROTACs are preferred in this disease area, drawbacks and lessons learnt from the past, the role of linkers in establishing crucial degradation, findings, pharmacokinetics, parameters, limitations of PROTACs in clinical settings, and future outcomes.

摘要

根据文献中越来越多的证据,促炎介质/靶点会激活多种信号通路,引发最终导致急性疼痛、慢性炎症性疾病和多种自身免疫性疾病的病症。由于蛋白水解靶向嵌合体(PROTACs)有望克服传统疗法的局限性,传统药物已被排除在外。这些异双功能分子通过泛素化作用帮助降解目标蛋白。本综述涵盖了PROTACs在炎症介导和自身免疫靶点方面的现状和未来发展。重点突出并讨论了不同的关键点,例如为什么PROTACs在该疾病领域更受青睐、过去的缺点和经验教训、连接子在建立关键降解中的作用、研究结果、药代动力学参数、PROTACs在临床环境中的局限性以及未来前景。

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本文引用的文献

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PROTACs: A novel strategy for cancer drug discovery and development.PROTACs:癌症药物发现与开发的新策略。
MedComm (2020). 2023 May 29;4(3):e290. doi: 10.1002/mco2.290. eCollection 2023 Jun.
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Pathogenesis of autoimmune disease.自身免疫性疾病的发病机制。
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ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer.ARE-蛋白酶靶向嵌合体可实现Nrf2-MafG异二聚体的共降解。
J Med Chem. 2023 May 11;66(9):6070-6081. doi: 10.1021/acs.jmedchem.2c01909. Epub 2023 Mar 9.
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Advancing targeted protein degradation for metabolic diseases therapy.推进靶向蛋白降解治疗代谢疾病。
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