Novel enzyme inhibitor paves way for new c...(have proven useful as therapeutic agents...),Health

To overcome this hurdle and develop an inhibitor with greater specificity, and therefore greater potential as a drug candidate, Marmorstein and his colleagues set out to create a lipid kinase inhibitor using a metal complex in its structure.

Though most protein inhibitors are created using purely organic atomssuch as carbon, nitrogen, oxygen and sulfuradding a metal to the mix allows one to create compounds that are otherwise impossible to make with a purely organic toolbox, Marmorstein says.

The metal not only lends a structural support to the inhibitor but also provides the ability to form and accept a wider range of ligands, or chemical building blocks, to increase kinase selectivity, he says.

Working with Eric Meggers of the University of Pennsylvania (now at the Philipps-Universtat Marburg in Germany), who has developed organometallic enzyme inhibitors for other types of kinases, the scientists combined traditional organic compounds with the metal Ruthenium to create a novel scaffold, the platform on which the inhibitor was constructed.

After screening a general organometallic library of compounds designed by Meggers to identify potential agents to inhibit PI3K, the scientists identified a protein kinase inhibitor known as DW2.

The scientists then used X-ray crystallography to determine the three-dimensional structure of PI3K bound to DW2, using the structure as a starting point to fashion more effective PI3K inhibitors.

Based on what they had observed in their structural studies, the scientists were able to make several changes to the inhibitor to prepare a more potent and selective agent, Marmorstein says.

To determine how well their new inhibitor, called E5, could selectively target PI3K lipid kinases, the researchers tested the agent on five different human protein kinases representing four kinase families. The study showed E5 selec
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