Zhu Gui-Dong, Gong Jianchun, Gandhi Viraj B, Woods Keith, Luo Yan, Liu Xuesong, Guan Ran, Klinghofer Vered, Johnson Eric F, Stoll Vincent S, Mamo Mulugeta, Li Qun, Rosenberg Saul H, Giranda Vincent L
Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA.
Bioorg Med Chem. 2007 Mar 15;15(6):2441-52. doi: 10.1016/j.bmc.2007.01.010. Epub 2007 Jan 17.
Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.
与蛋白激酶A（PKA）相比，苏氨酸-211是蛋白激酶B/Akt激酶结构域中三个不同的氨基酸残基之一，PKA是同一AGC家族中密切相关的类似物。为了提高我们的吲唑-吡啶系列Akt抑制剂相对于PKA的效力和选择性，研究工作集中在引入一种化学官能团以与苏氨酸-211的羟基相互作用。在吲唑骨架的C-6位引入了几个取代基，包括氧阴离子、氨基和硝基，导致Akt效力显著下降。在同一位置（即9f）的苯环中引入一个氮原子保持了Akt活性，并且在某些情况下提高了对PKA的选择性。还讨论了新型吡啶-吡唑并吡啶系列Akt抑制剂的构效关系及其与PKA结合时的结构特征。
