882169-91-7Relevant 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.
Discovery of trans-3,4′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation
Li, Qun,Li, Tongmei,Zhu, Gui-Dong,Gong, Jianchun,Claibone, Akiyo,Dalton, Chris,Luo, Yan,Johnson, Eric F.,Shi, Yan,Liu, Xuesong,Klinghofer, Vered,Bauch, Joy L.,Marsh, Kennan C.,Bouska, Jennifer J.,Arries, Shannon,De Jong, Ron,Oltersdorf, Tilman,Stoll, Vincent S.,Jakob, Clarissa G.,Rosenberg, Saul H.,Giranda, Vincent L.
, p. 1679 - 1685 (2007/10/03)
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4′-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC50 values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity
Zhu, Gui-Dong,Gong, Jianchun,Claiborne, Akiyo,Woods, Keith W.,Gandhi, Viraj B.,Thomas, Sheela,Luo, Yan,Liu, Xuesong,Shi, Yan,Guan, Ran,Magnone, Shayna R.,Klinghofer, Vered,Johnson, Eric F.,Bouska, Jennifer,Shoemaker, Alexander,Oleksijew, Anatol,Stoll, Vincent S.,Jong, Ron De,Oltersdorf, Tilman,Li, Qun,Rosenberg, Saul H.,Giranda, Vincent L.
, p. 3150 - 3155 (2007/10/03)
The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t1/2 = 0.3 h, po F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t1/2 = 5.0 h, po F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
Kinase inhibitors
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Page/Page column 16, (2010/01/31)
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.
