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.
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 K(i) 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.
Tong
Yunsong
Y
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, R47S, AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com
Stewart
Kent D
KD
Thomas
Sheela
S
Przytulinska
Magdalena
M
Johnson
Eric F
EF
Klinghofer
Vered
V
Leverson
Joel
J
McCall
Owen
O
Soni
Niru B
NB
Luo
Yan
Y
Lin
Nan-horng
NH
Sowin
Thomas J
TJ
Giranda
Vincent L
VL
Penning
Thomas D
TD
D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007555:Isoxazoles; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1