Rational Design of Phosphoinositide 3-Kinase 伪 Inhibitors That Exhibit Selectivity over the Phosphoinositide 3-Kinase 尾 Isoform

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• 作者：Timothy P. Heffron ; BinQing Wei ; Alan Olivero ; Steven T. Staben ; Vickie Tsui ; Steven Do ; Jennafer Dotson ; Adrian J. Folkes ; Paul Goldsmith ; Richard Goldsmith ; Janet Gunzner ; John Lesnick ; Cristina Lewis ; Simon Mathieu ; Jim Nonomiya ; Stephen Shuttleworth ; Daniel P. Sutherlin ; Nan Chi Wan ; Shumei Wang ; Christian Wiesmann ; Bing-Yan Zhu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 24, 2011
• 年：2011
• 卷：54
• 期：22
• 页码：7815-7833
• 全文大小：614K
• 年卷期：v.54,no.22(November 24, 2011)
• ISSN：1520-4804

文摘

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3K伪 has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3K伪 vs PI3K尾 selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3K伪 that is not attained with the corresponding Lys777 of PI3K尾. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.