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 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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Tong Y,Stewart KD,Thomas S,Przytulinska M,Johnson EF,Klinghofer V,Leverson J,McCall O,Soni NB,Luo Y,Lin NH,Sowin TJ,Giranda VL,Penning TDdoi
10.1016/j.bmcl.2008.08.079subject
Has Abstractpub_date
2008-10-01 00:00:00pages
5206-8issue
19eissn
0960-894Xissn
1464-3405pii
S0960-894X(08)01011-1journal_volume
18pub_type
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