AstraZeneca Pharmaceuticals , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.
J Med Chem. 2012 Jun 14;55(11):5003-12. doi: 10.1021/jm3004043. Epub 2012 May 21.
The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.
设计选择性抑制单一激酶的化合物是一项重大挑战，尤其是对于结合 ATP 结合位点的化合物而言。我们在这里描述了如何利用蛋白质-配体晶体结构信息来合理化观察到的选择性，并指导更具选择性的化合物的设计。在鉴定 FGFR 选择性抑制剂的过程中，通过酶和细胞筛选获得的抑制数据以及一系列配体的晶体结构，为这一过程提供了逐步说明。通过以特定方式增加配体在特定区域的大小，从而在主要靶标中被容忍而不在其他相关激酶中被容忍，利用了空间效应。激酶是利用这种方法的极好的靶标类别，因为它们的活性形式具有保守的折叠和较小的侧链移动性。
