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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4296-4302
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Beschreibung
Zusammenfassung:	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