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Scientists at The Wistar Institute have developed a new type of enzyme inhibitor capable of blocking a biochemical pathway that plays a key role in cancer development.
Based on studies in human melanoma cells, the research paves the way for developing new ways to treat cancer by dampening the overactive enzyme activity that leads to uncontrolled tumour growth.
Details of the study, to be published in the 16 May issue of the journal ACS Chemical Biology, show how small-molecule inhibitors can be designed to target a family of signaling proteins, called phosphatidyl-inositol-3-kinases, or PI3Ks.
“The PI3K pathway has been called the most mutated pathway in human cancer,” says Ronen Marmorstein, PhD, a professor in the Gene Expression and Regulation Program at Wistar and senior author of the study.
Kinases have been the focus of drug development strategies for years, with some protein kinase-inhibiting compounds, such as Gleevec, already being used clinically to inhibit tumour growth. Though pharmaceutical companies have a keen interest in developing similar types of inhibitors for lipid kinases, targeting these enzymes remains a challenge.
The problem is, the drugs often lack specificity, Marmorstein says. Such broad-spectrum compounds, which inhibit many different but related kinases, inevitably cause side-effects and are therefore poor drug candidates. For these reasons, none of the PI3K-inhibitors developed to date have proven useful as therapeutic agents, he says.
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 atoms – such as carbon, nitrogen, oxygen and sulfur – adding a metal to the mix allows one to create compounds that are otherwise impossible to make with a purely organic toolbox, Marmorstein says.