Title of article :
Isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones as unique, potent and selective inhibitors for Pim-1 and Pim-2 kinases: Chemistry, biological activities, and molecular modeling
Author/Authors :
Yunsong Tong، نويسنده , , Kent D. Stewart، نويسنده , , Sheela Thomas، نويسنده , , Magdalena Przytulinska، نويسنده , , Eric F. Johnson، نويسنده , , Vered Klinghofer، نويسنده , , Joel Leverson، نويسنده , , J. Owen McCall، نويسنده , , Niru B. Soni، نويسنده , , Yan Luo، نويسنده , , Nan-Horng Lin، نويسنده , , Thomas J. Sowin، نويسنده , , Vincent L. Giranda، نويسنده , , Thomas D. Penning، نويسنده ,
Abstract :
A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure–activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with Ki values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
