Potent and selective inhibitors of PI3K¦Ä: Obtaining isoform selectivity from the affinity pocket and tryptophan shelf

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• 作者：Daniel P. Sutherlin^a ; ^{sutherd1@gene.com} ; Stewart Baker^b ; Angelina Bisconte^a ; Paul M. Blaney^c ; Anthony Brown^b ; Bryan K. Chan^a ; David Chantry^a ; Georgette Castanedo^a ; Paul DePledge^b ; Paul Goldsmith^b ; David M. Goldstein^d ; Timothy Hancox^b ; Jasmit Kaur^b ; David Knowles^b ; Rama Kondru^d ; John Lesnick^a ; Matthew C. Lucas^d ; Cristina Lewis^a ; Jeremy Murray^a ; Alan J. Nadin^c ; Jim Nonomiya^a ; Jodie Pang^a ; Neil Pegg^b ; Steve Price^c ; Karin Reif^a ; Brian S. Safina^a ; Laurent Salphati^a ; Steven Staben^a ; Eileen M. Seward^c ; Stephen Shuttleworth^b ; Sukhjit Sohal^b ; Zachary K. Sweeney^a ; Mark Ultsch^a ; Bohdan Waszkowycz^c ; Binqing Wei^a
• 关键词：LYZRRJHRJOTSRW-UHFFFAOYSA-N
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 July, 2012
• 年：2012
• 卷：22
• 期：13
• 页码：4296-4302
• 全文大小：1531 K

文摘

A potent inhibitor of PI3K¦Ä that is ?00 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 PI3K¦Ã. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.