Rezende Miranda Renata, Zhang Chao
Department of Chemistry, Loker Hydrocarbon Research Institute, University of Southern California Los Angeles California 90089 USA
Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology Rochester New York 14623 USA.
RSC Med Chem. 2022 Mar 30;13(7):783-797. doi: 10.1039/d1md00389e. eCollection 2022 Jul 20.
The human protein kinase superfamily comprises over 500 members that operate in nearly every signal transduction pathway and regulate essential cellular processes. Deciphering the functional roles of protein kinases with small-molecule inhibitors is essential to enhance our understanding of cell signaling and to facilitate the development of new therapies. However, it is rather challenging to identify selective kinase inhibitors because of the conserved nature of the ATP binding site. A number of chemical-genetic approaches have been developed during the past two decades to enable selective chemical perturbation of the activity of individual kinases. Herein, we review the development and application of chemical-genetic strategies that feature the use of covalent inhibitors targeting cysteine residues to dissect the cellular functions of protein kinases.
人类蛋白激酶超家族由500多个成员组成，它们几乎参与了每条信号转导途径，并调节细胞的基本过程。利用小分子抑制剂来阐明蛋白激酶的功能作用，对于增进我们对细胞信号传导的理解以及推动新疗法的开发至关重要。然而，由于ATP结合位点的保守性，鉴定选择性激酶抑制剂颇具挑战性。在过去二十年中，人们开发了许多化学遗传学方法，以实现对单个激酶活性的选择性化学干扰。在此，我们综述了化学遗传学策略的发展与应用，这些策略的特点是使用靶向半胱氨酸残基的共价抑制剂来剖析蛋白激酶的细胞功能。
