Author/Authors :
Gui-Dong Zhu، نويسنده , , Jianchun Gong، نويسنده , , Akiyo Claiborne، نويسنده , , Keith W. Woods، نويسنده , , Viraj B. Gandhi، نويسنده , , Sheela Thomas، نويسنده , , Yan Luo، نويسنده , , Xuesong Liu، نويسنده , , Yan Shi، نويسنده , , Ran Guan، نويسنده , , Shayna R. Magnone، نويسنده , , Vered Klinghofer، نويسنده , , Eric F. Johnson، نويسنده , , Jennifer Bouska، نويسنده , , Alexander Shoemaker، نويسنده , , Anatol Oleksijew، نويسنده , , Vincent S. Stoll، نويسنده , , Ron De Jong، نويسنده , , Tilman Oltersdorf، نويسنده , , Qun Li، نويسنده , , et al.، نويسنده ,
Abstract :
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.
Keywords :
FL5.12-Akt , protein kinase B , GSK3 , anticancer , Akt inhibitor , PKB
