552323-91-8Relevant academic research and scientific papers
Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors
Woods, Keith W.,Fischer, John P.,Claiborne, Akiyo,Li, Tongmei,Thomas, Sheela A.,Zhu, Gui-Dong,Diebold, Robert B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Han, Edward K.,Guan, Ran,Magnone, Shayna R.,Johnson, Eric F.,Bouska, Jennifer J.,Olson, Amanda M.,Jong, Ron de,Oltersdorf, Tilman,Luo, Yan,Rosenberg, Saul H.,Giranda, Vincent L.,Li, Qun
, p. 6832 - 6846 (2007/10/03)
A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (Ki = 0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
Synthesis and structure-activity relationship of 3,4′- bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer
Li, Qun,Woods, Keith W.,Thomas, Sheela,Zhu, Gui-Dong,Packard, Garrick,Fisher, John,Li, Tongmei,Gong, Jianchun,Dinges, Jurgen,Song, Xiaohong,Abrams, Jason,Luo, Yan,Johnson, Eric F.,Shi, Yan,Liu, Xuesong,Klinghofer, Vered,Des Jong, Ron,Oltersdorf, Tilman,Stoll, Vincent S.,Jakob, Clarissa G.,Rosenberg, Saul H.,Giranda, Vincent L.
, p. 2000 - 2007 (2007/10/03)
Structure-based design and synthesis of the 3,4′-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC50 of 1.3 nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC50 values of 0.42 and 0.59 μM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC50 of 1.5 μM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.
Kinase inhibitors
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, (2008/06/13)
Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
