ACS Chem Biol. 2008 May 16;3(5):305-16.

Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity.

Xie P, Williams DS, Atilla-Gokcumen GE, Milk L, Xiao M, Smalley KS, Herlyn M, Meggers E, Marmorstein R.

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Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.

PMID:: 18484710; [PubMed - indexed for MEDLINE]

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Structures reported by this article

Crystal Structure Of Pi3k P110gamma Catalytical Domain In Complex With Organoruthenium Inhibitor Dw2

PDB: 3CSF

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.8 Å

See all 2 structures...

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