Potent and selective inhibitors of PI3Kδ: Obtaining isoform selectivity from the affinity pocket and tryptophan shelf

A potent inhibitor of PI3Kδ that is ⩾200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Phar...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4296-4302
Main Authors: Sutherlin, Daniel P., Baker, Stewart, Bisconte, Angelina, Blaney, Paul M., Brown, Anthony, Chan, Bryan K., Chantry, David, Castanedo, Georgette, DePledge, Paul, Goldsmith, Paul, Goldstein, David M., Hancox, Timothy, Kaur, Jasmit, Knowles, David, Kondru, Rama, Lesnick, John, Lucas, Matthew C., Lewis, Cristina, Murray, Jeremy, Nadin, Alan J., Nonomiya, Jim, Pang, Jodie, Pegg, Neil, Price, Steve, Reif, Karin, Safina, Brian S., Salphati, Laurent, Staben, Steven, Seward, Eileen M., Shuttleworth, Stephen, Sohal, Sukhjit, Sweeney, Zachary K., Ultsch, Mark, Waszkowycz, Bohdan, Wei, Binqing
Format: Article
Language:English
Subjects:
Animals
B-cell inhibition
Binding Sites
Biological and medical sciences
Computer Simulation
crystal structure
Female
in vivo studies
Injections, Intravenous
Liver - metabolism
Male
Medical sciences
Mice
Mice, Inbred BALB C
mutants
Mutation
pharmacokinetics
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
phosphotransferases (kinases)
PI3K delta inhibitor
PI3K Isoform selectivity
Protein Isoforms - antagonists & inhibitors
Protein Isoforms - genetics
Protein Isoforms - metabolism
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Rhumatoid arthritis
Structure-Activity Relationship
structure-activity relationships
tryptophan
Tryptophan - chemistry
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Summary:A potent inhibitor of PI3Kδ that is ⩾200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.05.027