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

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.