Peng Xie1, Douglas S. Williams2, G. Ekin Atilla-Gokcumen1, Leslie Milk3, Min Xiao1, Keiran S.M. Smalley1, Meenhard Herlyn1, Eric Meggers2, and Ronen Marmorstein4. (1) The Wistar Institute, University of Pennsylvania, Philadelphia, PA, (2) University of Pennsylvania, Philadelphia, PA, (3) Graduate Group in Biochemistry and Molecular Biophysics, School of Medicine, Philadelphia, PA, (4) The Wistar Institute, N/a, PA
Mutations that constitutively activate the PI3K signaling pathway,including alterations in PI3K, PTEN and AKT are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other related diseases. In this study, we report on the combination of a novel organometallic kinase inhibitor scaffold with structure-based design to develop a PI3K inhibitor, called E5E2, with an IC50 potency in the mid-low-nanomolar range and selectivity against a panel of protein kinases. We also show that E5E2 inhibits phospho-AKT in human melanoma cells and leads to growth inhibition. Consistent with a role for the PI3K pathway in tumor cell invasion, E5E2 treatment also inhibits the migration of melanoma cells in a 3D spheroid assay. The structure of the PI3K�/E5E2 complex reveals the molecular features that give rise to this potency and selectivity towards lipid kinases with implications for the design of a subsequent generation of PI3K-isoform specific organometallic inhibitors.