Fabbro Doriano, Cowan-Jacob Sandra W, Moebitz Henrik
PIQUR Therapeutics, Basel, Switzerland.
Novartis Institutes of Biomedical Research, Basel, Switzerland.
Br J Pharmacol. 2015 Jun;172(11):2675-700. doi: 10.1111/bph.13096. Epub 2015 Mar 24.
Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on 'the 10 things you should know about protein kinases and their inhibitors', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the '10 things' have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncological indications.
许多人类恶性肿瘤与蛋白质或脂质激酶的异常调节有关，这是由突变、染色体重排和/或基因扩增引起的。蛋白质和脂质激酶是治疗人类疾病的重要靶点类别。本综述聚焦于“关于蛋白激酶及其抑制剂你应该了解的十件事”，包括对蛋白激酶及其抑制剂历史的简短介绍，并以激酶药物发现的展望作为结尾。尽管这“十件事”在一定程度上是任意选择的，但它们全面涵盖了激酶药物发现过去和现在的努力，并总结了当前激酶抑制剂的现状以及关于激酶结构和结合模式的知识。除了描述蛋白激酶抑制剂作为药物的潜力外，本综述还关注它们的局限性，特别是在肿瘤适应症中如何规避对激酶抑制剂新出现的耐药性。
