Technische Universität Dortmund, Fakultät Chemie - Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
ACS Chem Biol. 2013 Jan 18;8(1):58-70. doi: 10.1021/cb300663j. Epub 2012 Dec 31.
The modulation of kinase function has become an important goal in modern drug discovery and chemical biology research. In cancer-targeted therapies, kinase inhibitors have been experiencing an upsurge, which can be measured by the increasing number of kinase inhibitors approved by the FDA in recent years. However, lack of efficacy, limited selectivity, and the emergence of acquired drug resistance still represent major bottlenecks in the clinic and challenge inhibitor development. Most known kinase inhibitors target the active kinase and are ATP competitive. A second class of small organic molecules, which address remote sites of the kinase and stabilize enzymatically inactive conformations, is rapidly moving to the forefront of kinase inhibitor research. Such allosteric modulators bind to sites that are less conserved across the kinome and only accessible upon conformational changes. These molecules are therefore thought to provide various advantages such as higher selectivity and extended drug target residence times. This review highlights various strategies that have been developed to utilizing exclusive structural features of kinases and thereby modulating their activity allosterically.
激酶功能的调节已成为现代药物发现和化学生物学研究的重要目标。在癌症靶向治疗中，激酶抑制剂的应用呈上升趋势，近年来 FDA 批准的激酶抑制剂数量不断增加，即可见一斑。然而，疗效不佳、选择性有限以及获得性药物耐药性的出现仍然是临床治疗的主要瓶颈，也是抑制剂开发的挑战。大多数已知的激酶抑制剂针对的是活性激酶，且为 ATP 竞争性抑制剂。第二类小分子有机化合物针对激酶的远程位点，并稳定酶失活构象，它们正在迅速成为激酶抑制剂研究的前沿。这种别构调节剂结合在激酶家族中保守性较差的位点，只有在构象发生变化时才能够结合。因此，这些分子被认为具有更高的选择性和延长药物靶标停留时间等各种优势。本综述重点介绍了各种已经开发的策略，这些策略利用了激酶的独特结构特征，从而能够别构调节其活性。
