Department of Pharmaceutical Science, University of Bologna, Italy.
Curr Med Chem. 2010;17(25):2804-21. doi: 10.2174/092986710791859333.
Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.
蛋白激酶是肿瘤药物研发中一个有吸引力的靶点。大多数激酶抑制剂都是 ATP 竞争性抑制剂，称为 I 型抑制剂。ATP 结合口袋在激酶家族成员中高度保守，很难找到选择性的药物。此外，ATP 竞争性抑制剂必须与细胞内高浓度的 ATP 竞争，导致生化测定和细胞测定的 IC50 之间存在差异。非 ATP 竞争性抑制剂，称为 II 型和 III 型抑制剂，提供了克服这些问题的可能性。这些抑制剂通过诱导靶酶的构象变化而起作用，使激酶不再能够发挥作用。在 DFG-out 形式中，苯丙氨酸侧链移动到一个新的位置。这种运动产生了一个可供抑制剂占据的疏水性口袋。这些抑制剂具有一些共同的特征。它们包含一个杂环系统，与激酶铰链残基形成一个或两个氢键。它们还包含一个疏水性部分，占据由 DFG 基序中的苯丙氨酸移位形成的口袋。此外，所有抑制剂都具有氢键供体-受体对，通常是脲或酰胺，将铰链结合部分与疏水性部分连接起来，并与变构部位相互作用。有许多种非 ATP 竞争性抑制剂可用于各种激酶。本文综述了能够诱导 DFG-out 构象的小分子，特别是重点介绍了结构特征、SAR 和生物学特性。
