title: Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity.
abstract: Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (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 IC 50 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 PI3Kgamma/E5E2 complex reveals the molecular features that give rise to this potency and selectivity toward lipid kinases with implications for the design of a subsequent generation of PI3K-isoform-specific organometallic inhibitors.
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williams
authors.forename: G Ekin
authors.initials: GE
authors.lastname: Atilla-Gokcumen
authors.forename: Leslie
authors.initials: L
authors.lastname: Milk
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012428:Ruthenium