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.