Structural Basis of Mechanisms of Activation and Inhibition of PI3Kα Signaling Pathway

The PI3K-AKT signaling pathway is one of the most frequently dysregulated pathways in human cancers. Our goal is to design precision cancer therapies that target mutant PI3Kα, the lipid kinase that controls blood sugar levels, new blood vessel formation, and how cells grow and move. Mutations in PI3Kα, present in about 20% of the cancers, result in dysregulated cell growth and tumor progression. We seek to understand the structural differences between wild-type and oncogenic mutant PI3Kα to discover small molecules that bind to novel sites, rather than to canonical ATP-competitive sites. A detailed understanding of the mechanistic differences between wt and mutant PI3Kα will help in discovering novel drugs that are able to selectively “switch off” the mutant protein without affecting normal cellular functions.