Wang Qi, Zorn Julie A, Kuriyan John
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, California, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, California, USA; Howard Hughes Medical Institute, University of California, Berkeley, California, USA; Department of Chemistry, University of California, Berkeley, California, USA; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Methods Enzymol. 2014;548:23-67. doi: 10.1016/B978-0-12-397918-6.00002-1.
The aberrant activation of protein kinases is associated with many human diseases, most notably cancer. Due to this link between kinase deregulation and disease progression, kinases are one of the most targeted protein families for small-molecule inhibition. Within the last 15 years, the U.S. Food and Drug Administration has approved over 20 small-molecule inhibitors of protein kinases for use in the clinic. These inhibitors target the kinase active site and represent the successful hurdling by medicinal chemists of the formidable challenge posed by the high similarity among the active sites of the approximately 500 human kinases. We review the conserved structural features of kinases that are important for inhibitor binding as well as for catalysis. Many clinically approved drugs elicit selectivity by exploiting subtle variation within the kinase active site. We highlight some of the crystallographic studies on the kinase-inhibitor complexes that have provided valuable guidance for the development of these drugs as well as for future drug design efforts.
蛋白激酶的异常激活与许多人类疾病相关，最显著的是癌症。由于激酶失调与疾病进展之间的这种联系，激酶是小分子抑制作用最具靶向性的蛋白家族之一。在过去15年里，美国食品药品监督管理局已批准20多种蛋白激酶小分子抑制剂用于临床。这些抑制剂靶向激酶活性位点，代表了药物化学家成功跨越了由约500种人类激酶活性位点高度相似性所带来的巨大挑战。我们综述了激酶对于抑制剂结合以及催化作用很重要的保守结构特征。许多临床批准的药物通过利用激酶活性位点内的细微差异来实现选择性。我们重点介绍了一些关于激酶-抑制剂复合物的晶体学研究，这些研究为这些药物的开发以及未来的药物设计工作提供了有价值的指导。
