小分子
体内
蛋白质水解
蛋白质降解
限制
药物发现
化学
靶蛋白
细胞生物学
功能(生物学)
蛋白质功能
机制(生物学)
计算生物学
生物化学
生物
酶
生物技术
物理
工程类
基因
机械工程
量子力学
作者
Momar Toure,Craig M. Crews
标识
DOI:10.1002/anie.201507978
摘要
Abstract The current inhibitor‐based approach to therapeutics has inherent limitations owing to its occupancy‐based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off‐target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event‐driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small‐molecule‐based proteolysis‐targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.
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