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Paris, July 23, 2008

Could metals help treat cancer ?

A fruitful collaboration between chemists and biologists has made it possible to identify the effects of a new class of molecules, polyoxometalates (1), primarily composed of metals and oxygen. These molecules are very powerful inhibitors of a specific protein kinase, CK2, an enzyme that is overactive in a number of cancers. The enzyme's instrumental role in controlling cell proliferation and survival makes it an important target in the search for new medications. These results have just been published in the journal Chemistry and Biology by chemists from the Institut de chimie moléculaire (CNRS / UPMC) and biologists from the Institut de recherche en technologies et sciences pour le vivant (iRTSV, CEA de Grenoble / CNRS / Inserm.)

Phosphorylation enzymes (2) , which include the protein kinase CK2, play a critical role in controlling cell proliferation. Deregulated protein kinase activity is implicated in a number of cancers, which has led to a recent surge in research on molecules that can inhibit the activity of these enzymes. The currently known CK2 inhibitors are all organic compounds that neutralize enzymatic activity by binding to its active site (3).

The contribution of the study carried out by the researchers at the Institut de chimie moléculaire and the Institut de recherche en technologies et sciences pour le vivant was to reveal a new class of CK2 inhibitors. The new inhibitors are inorganic molecules, polyoxometalates (POMs), primarily made up of metals (molybdenum and tungsten) and oxygen. They are the most powerful CK2 inhibitors yet discovered, working at very low (nanomolar) concentrations. In addition, the researchers showed that the mode of action of POMs, although not yet fully understood, is completely new. Unlike organic inhibitors, POMs do not bind to the active site of the enzyme.

This work opens up several areas for further research: clarifying the mechanism of action of these new molecules, finding the minimum molecular entity that can inhibit enzyme activity, and finally, given its importance in the health field, improving knowledge of how the enzyme CK2 works. In the longer term, these results could pave the way for new approaches to developing anti-cancer drugs.

Structure of the protein kinase CK2 (left) and the structures of different polyoxometalate (POM) molecules (right).

© B. Hasenknopf

Structure of the protein kinase CK2 (left) and the structures of different polyoxometalate (POM) molecules (right).



Notes:

(1) Polyoxometalates are anionic inorganic metal oxide structures that have valuable catalytic properties.
(2) Phosphorylation enzymes called protein kinases can attach a phosphate group to proteins that may be inactive enzymes. The addition of the phosphate group can activate these “silent” enzymes. Protein kinases thus play a central role in controlling the activity of numerous enzymes in the cell.
(3) The active site of an enzyme is a particular region where the substrates bind together and enzymatic reactions takes place.

References:

Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2, Renaud Prudent, Virginie Moucadel, Béatrice Laudet, Caroline Barette, Laurence Lafanechère, Bernold Hasenknopf, Joaquim Li, sébastian Bareyt, Emmanuel Lacôte, Serge Thorimbert, Max Malacria, Pierre Gouzerh, Claude Cochet, Chemistry and Biology, July 21, 2008.

Contact information:

Researchers
CNRS -Institut de chimie moléculaire
Bernold Hasenknopf
33 6 33 11 60 78
bernold.hasenknopf@upmc.fr

CEA - iRTSV
Claude Cochet, Inserm senior researcher
04 38 78 42 04
ccochet1@cea.fr

Public Information Officers
CNRS
Céline Lipari
01 44 96 51 51
celine.lipari@cnrs-dir.fr


CEA
Damien Larroque
01 64 50 20 97
Damien.larroque@cea.fr

UPMC
Claire de Thoisy-Méchin
01. 44. 27. 23. 34.
claire.de_thoisy-mechin@upmc.fr

Inserm
Priscille Rivière
01 44 23 60 97
presse@inserm.fr


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