Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges.
Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges.
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DOI：
10.1021/cb5008376
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发表时间：
2015-01-16
影响因子：
4
通讯作者：
Soellner, Matthew B.
中科院分区：
文献类型：
--
作者：
Breen, Meghan E.;Soellner, Matthew B.
蛋白激酶是细胞通讯的重要介质和许多疾病的有吸引力的药物靶点。虽然开发ATP竞争性激酶抑制剂已经取得了成功，但ATP竞争性抑制剂的缺点导致人们对ATP结合口袋外靶向位点的兴趣增加。底物竞争性，ATP非竞争性结合模式的激酶抑制剂是有前途的，由于增加的选择性和更好的协议之间的生物化学和体外效力的可能性。然而，鉴定这些类型的抑制剂的困难导致与ATP竞争性抑制剂相比，报道的小分子底物磷酸化位点抑制剂显著较少。本文综述了底物磷酸化位点抑制剂和可用于发现此类抑制剂的方法，包括讨论这些筛选方法所固有的挑战。
Protein kinases are important mediators of cellular communication and attractive drug targets for many diseases. Although success has been achieved with developing ATP-competitive kinase inhibitors, the disadvantages of ATP-competitive inhibitors have led to increased interest in targeting sites outside of the ATP binding pocket. Kinase inhibitors with substrate-competitive, ATP-noncompetitive binding modes are promising due to the possibility of increased selectivity and better agreement between biochemical and in vitro potency. However, the difficulty of identifying these types of inhibitors has resulted in significantly fewer small molecule substrate phosphorylation site inhibitors being reported compared to ATP-competitive inhibitors. This review surveys reported substrate phosphorylation site inhibitors and methods that can be applied to the discovery of such inhibitors, including a discussion of the challenges inherent to these screening methods.
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