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

@article{Heffron2011RationalDO,
  title={Rational design of phosphoinositide 3-kinase α inhibitors that exhibit selectivity over the phosphoinositide 3-kinase β isoform.},
  author={Timothy Heffron and BinQing Wei and Alan G. Olivero and Steven T Staben and Vickie Tsui and Steven Do and Jennafer Dotson and Adrian J Folkes and Paul S. Goldsmith and Richard Goldsmith and Janet L. Gunzner and John D Lesnick and Cristina Lewis and Simon Mathieu and Jim Nonomiya and Stephen J. Shuttleworth and Daniel P. Sutherlin and Nan Chi Wan and Shumei Wang and Christian Wiesmann and Bing-yan Zhu},
  journal={Journal of medicinal chemistry},
  year={2011},
  volume={54 22},
  pages={
          7815-33
        }
}
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… CONTINUE READING