929617-33-4Relevant academic research and scientific papers
Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt
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.
, p. 2441 - 2452 (2007/10/03)
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.
