Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Institute for Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Strasse 9, 60438, Frankfurt am Main, Germany.
Angew Chem Int Ed Engl. 2018 Apr 9;57(16):4372-4385. doi: 10.1002/anie.201707875. Epub 2018 Feb 2.
Drugs that function through covalent bond formation represent a considerable fraction of our repository of effective medicines but safety concerns and the complexity of developing covalent inhibitors has rendered covalent targeting a less attractive strategy for rational drug design. The recent approval of four covalent kinase inhibitors and the development of highly potent covalent kinase probes with exceptional selectivity has raised significant interest in industry and academic research and validated the concept of covalent kinase targeting for clinical applications. The abundance of cysteines at diverse positions in and around the kinase active site suggests that a large fraction of kinases can be targeted by covalent inhibitors. Herein, we review recent developments of this rapidly growing area in kinase drug development and highlight the unique opportunities and challenges of this strategy.
通过共价键形成起作用的药物代表了我们有效药物库中的相当一部分，但安全问题和开发共价抑制剂的复杂性使得共价靶向成为一种不太有吸引力的合理药物设计策略。最近批准的四种共价激酶抑制剂和具有卓越选择性的高活性共价激酶探针的开发引起了业界和学术研究的极大兴趣，并验证了将共价激酶靶向用于临床应用的概念。激酶活性位点内部和周围的不同位置存在大量半胱氨酸，这表明可以用共价抑制剂来靶向很大一部分激酶。本文综述了激酶药物开发这一快速发展领域的最新进展，并强调了该策略的独特机遇和挑战。
