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早期评估口服递呈 PROTAC 以克服其分子挑战的机会。

Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges.

机构信息

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, USA.

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, USA.

出版信息

Drug Discov Today. 2024 Feb;29(2):103865. doi: 10.1016/j.drudis.2023.103865. Epub 2023 Dec 26.

DOI:10.1016/j.drudis.2023.103865
PMID:38154757
Abstract

PROteolysis TArgeting Chimeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are intractable to classic inhibitors. Heterobifunctional in nature, PROTACs are small molecules that offer a unique mechanism of protein degradation by hijacking the ubiquitin-mediated protein degradation pathway, known as the ubiquitin-proteasome system. Herein, we present an analysis on the structural characteristics of this novel chemical modality. Furthermore, we review and discuss the formulation opportunities to overcome the oral delivery challenges of PROTACs in drug discovery.

摘要

蛋白水解靶向嵌合体（PROTACs）通过靶向经典抑制剂难以靶向的蛋白质，为现代医学提供了新的机会。PROTACs 本质上是双功能的小分子，通过劫持泛素介导的蛋白质降解途径（称为泛素-蛋白酶体系统），提供了一种独特的蛋白质降解机制。在此，我们对这种新型化学模式的结构特征进行了分析。此外，我们还回顾和讨论了制剂机会，以克服药物发现中 PROTACs 的口服递送挑战。

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