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Researchers create first molecule blocks key component of cancer genes' on-off switch
Date:9/24/2010

ich instructions to begin or cease activity are inscribed.

The instructions themselves take the form of "bookmarks," substances placed on the chromatin by so-called epigenetic "writer" proteins. Another group of epigenetic proteins, known as "erasers," are able to remove the bookmarks. Both types of proteins have successfully been disabled by scientists, using molecules made in the lab or taken from nature. Their success has sparked intense interest in the development of anti-cancer therapies that work by blocking such proteins.

A third variety of epigenetic proteins potentially the most appealing as therapeutic targets, because they switch genes on or off by "reading" the bookmarks has received scant scientific attention. Bradner and his colleagues turned to this little-explored corner of biology by focusing on NMC cells.

The disease is caused by a chromosomal "translocation," in which two genes from different chromosomes become connected and give rise to an abnormal, fused protein known as BRD4-NUT. A review of the scientific literature suggested that some members of the benzodiazepine family of drugs, which includes Valium, Xanax and Ativan, are active against "bromodomain" proteins such as BRD4. With that as a clue, Bradner and his Dana-Farber colleague Jun Qi, PhD, created an array of molecules to see if any inhibited a "reader" protein of the BRD4-NUT gene. One did, quite convincingly a hybrid molecule, which researchers named JQ1, for Qi.

The investigators worked with researchers in the U.S. and overseas to learn more about the properties of JQ1 and how it works in cells. Stefan Knapp, PhD, of Oxford University in England, provided crystal-clear images of the molecule bound to a protein; Olaf Wiest, PhD, of the University of Notre Dame, showed that the molecule is less flexible in the presence of a protein, explaining why it so effectively blocks the protein; and Andrew Kung, MD, PhD, of Dana-Farber, engineer
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Contact: Teresa Herbert
teresa_herbert@dfci.harvard.edu
617-632-4090
Dana-Farber Cancer Institute
Source:Eurekalert

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