2. Academic Validation
  3. Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform

Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform

  • J Med Chem. 2011 Nov 24;54(22):7815-33. doi: 10.1021/jm2007084.
Timothy P Heffron 1,  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
Affiliations

Affiliation

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States. theffron@gene.com
PMID: 21985639 DOI: 10.1021/jm2007084
Abstract

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.

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