American Chemical Society
jm2007084_si_001.pdb (1.1 MB)

Rational Design of Phosphoinositide 3-Kinase α Inhibitors That Exhibit Selectivity over the Phosphoinositide 3-Kinase β Isoform

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posted on 2011-11-24, 00:00 authored by 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
Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ 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 PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. 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.