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839 a.a.
 ATP |
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 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate |
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 ADP |
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 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate |
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Key reference
DOI no: 10.1021/cb800039y Acs Chem Biol 3:305-316 (2008) PubMed id: 18484710
Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity. P.Xie, D.S.Williams, G.E.Atilla-Gokcumen, L.Milk, M.Xiao, K.S.Smalley, M.Herlyn, E.Meggers, R.Marmorstein. 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.
Literature references that cite this PDB file's key reference
PubMed id Reference
19225621 E.Meggers (2009).
Targeting proteins with metal complexes.Chem Commun (Camb), 0, 1001-1010.
19225663 T.J.Sundstrom, A.C.Anderson, and D.L.Wright (2009).
Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity.Org Biomol Chem, 7, 840-850.
19035373 G.E.Atilla-Gokcumen, N.Pagano, C.Streu, J.Maksimoska, P.Filippakopoulos, S.Knapp, and E.Meggers (2008).
Extremely tight binding of a ruthenium complex to glycogen synthase kinase 3.Chembiochem, 9, 2933-2936.
PDB code: 2jld The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
