Exploring the PI3Kα and γ binding sites with 2,6-disubstituted isonicotinic derivatives

A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kα and γ binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.

Using a homology model of PI3Kα based of PI3Kγ, a series of isonicotinic acid derivatives was designed and synthesized for studying the PI3Kα and γ active sites.Figure optionsDownload as PowerPoint slide