Kinetic Target-Guided Synthesis: Reaching the Age of Maturity
Kinetic Target-Guided Synthesis: Reaching the Age of Maturity
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DOI：
10.1021/acs.jmedchem.9b01183
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发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Deprez-Poulain, Rebecca
中科院分区：
文献类型：
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作者：
Bosc, Damien;Camberlein, Virgyl;Deprez-Poulain, Rebecca
动力学靶向合成（KTGS）是一种原始的发现策略，允许靶催化从试剂池中不可逆地合成其自身的配体。尽管它是在近二十年前开创的，但直到最近才证明了它在药物化学中的有用性，例如使用的蛋白质靶点数量越来越多，靶点和口袋类型范围更广，以及探索的治疗领域的多样性。近年来，发布了两种用于体内研究的新电极导线。酰胺化和多组分反应扩展了三唑形成之外的反应设备，并且还公开了两个新的在纤维素中的KTGS的实例。在此，我们分析了KTGS配体和弹头承载试剂的起源和化学空间。我们审查KTGS时间轴集中在最近的情况下，为了给药物化学家的全面范围内的这一战略，具有很大的潜力击中发现和击中或铅优化。
Kinetic target-guided synthesis (KTGS) is an original discovery strategy allowing a target to catalyze the irreversible synthesis of its own ligands from a pool of reagents. Although pioneered almost two decades ago, it only recently proved its usefulness in medicinal chemistry, as exemplified by the increasing number of protein targets used, the wider range of target and pocket types, and the diversity of therapeutic areas explored. In recent years, two new leads for in vivo studies were released. Amidations and multicomponent reactions expanded the armamentarium of reactions beyond triazole formation and two new examples of in cellulo KTGS were also disclosed. Herein, we analyze the origins and the chemical space of both KTGS ligands and warhead-bearing reagents. We review the KTGS timeline focusing on recent cases in order to give medicinal chemists the full scope of this strategy which has great potential for hit discovery and hit or lead optimization.