Potent and selective inhibitors of PI3KI': Obtaining isoform selectivity from the affinity pocket and tryptophan shelf

A potent inhibitor of PI3KI' that is aCO34200 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 P...

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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:
1-Phosphatidylinositol 3-kinase
Crystal structure
Data processing
Pharmacokinetics
Tryptophan
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Summary:A potent inhibitor of PI3KI' that is aCO34200 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 PI3KI3. 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
DOI:10.1016/j.bmcl.2012.05.027