Novel and selective spiroindoline-based inhibitors of sky kinase

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase. Structure determination using X-ray crystallography clearly demonstrates that the compounds bind in the canonical ATP-binding site yet exhibit high levels of kinome selectivity through the occupation of a uniq...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.190-193
Main Authors: Powell, Noel A., Kohrt, Jeffrey T., Filipski, Kevin J., Kaufman, Michael, Sheehan, Derek, Edmunds, Jeremy E., Delaney, Amy, Wang, Yuli, Bourbonais, Francis, Lee, Doh-Yeel, Schwende, Frank, Sun, Fang, McConnell, Pat, Catana, Cornel, Chen, Huifen, Ohren, Jeff, Perrin, Lisa A.
Format: Article
Language:English
Subjects:
Absorption
Adenosine Triphosphate - chemistry
Administration, Oral
Animals
Binding Sites
bioavailability
Biological and medical sciences
Biological Availability
chemistry
Chemistry, Pharmaceutical - methods
Crystal structure
Crystallography, X-Ray - methods
digestive system
Drug Design
Humans
Inhibitory Concentration 50
intestinal absorption
Intestines - drug effects
Kinase inhibitor
Medical sciences
Models, Chemical
Pharmacology. Drug treatments
Platelet Aggregation
Rats
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - chemistry
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Summary:We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase. Structure determination using X-ray crystallography clearly demonstrates that the compounds bind in the canonical ATP-binding site yet exhibit high levels of kinome selectivity through the occupation of a unique selectivity subpocket found adjacent to Ala571. Although novel and highly selective, inhibitors in this series exhibit modest oral bioavailability in the rat due to low absorption across the gut wall. We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.11.036