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Wrong proteins targeted in battle against cancer?

Researchers may be looking for novel cancer drugs in the wrong places, says Rockefeller University Professor James E. Darnell, Jr., M.D., in an article in this month's Nature Reviews Cancer.

Darnell, who received the 2002 Albert Lasker Award for Special Achievement in Medical Science, argues that drug development research should focus more on a specific group of proteins - called transcription factors - known to be overactive in almost all human cancers.

"The facts indicate that a limited number of transcription factors are indeed overactive in many cancers and that these overactive proteins themselves are appropriate drug targets," says Darnell, head of the Laboratory of Molecular Cell Biology at Rockefeller and co-author of the popular textbook Molecular Cell Biology.

These transcription factors include STAT3, discovered by Darnell and colleagues in 1994, STAT5, NF-kappaB, B-catenin, Notch, GLI and c-JUN - all of which play significant roles in a wide variety of cancers.

According to Darnell, drug developers continue to largely ignore these seemingly universal molecules of cancer because, unlike other cancer-causing proteins called protein kinases, transcription factors do not posses "active sites" or pockets that can be easily fitted with small inhibitory drugs.

Instead, drugs designed against transcription factors would have to target protein-protein interactions - which, because of their larger surface areas, are much harder to disrupt.

Still, Darnell argues that, despite inherent obstacles, such an approach could potentially yield novel cancer therapeutics.

"After all," he asks, "What is the benefit to medicine in all the twenty-first century promise of proteomics if we cannot selectively inhibit protein-protein interactions?"

Many of the transcription factors involved in cancer normally allow a healthy cell to respond to signals from the external environment by activating the "expression" of
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Contact: Whitney Clavin
clavinw@rockefeller.edu
212-327-7250
Rockefeller University
1-Oct-2002


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