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Molecular discovery suggests new strategy to fight cancer drug resistance
Date:6/20/2010

rapy drugs less effective. Developing drugs to specifically target survival proteins like MCL-1 has been challenging, but Walensky has been making progress on that front.

A small, coiled peptide unit called BH3, which is known as the "death domain," is a key interaction point between pro- and anti-apoptotic proteins. Walensky previously showed that an isolated BH3 coiled structure could be reinforced by chemical "staples" and targeted to the BH3-binding domains of BCL-2 survival proteins, causing the cancer cells in which they are overexpressed to self-destruct.

BH3 domains differ in subtle but important ways from one another, like a set of keys for different locks. Walensky said that molecular mimics of these domains are showing great promise in early clinical trials, yet most of these drugs block three or more BCL-2 family proteins, rather than homing in on one specific cancer-causing target. "An ideal pharmacologic toolbox would contain agents that target individual BCL-2 family proteins, subsets, and all members," explained Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.

In the current research, Walensky and Stewart searched through BH3 domains in cells hoping to find one that could bind to MCL-1 but no other protein and serve as a specific inhibitor of this formidable cancer protein. After combing a collection of BH3 domains, it turned out the one they were looking for was right in front of their eyes the BH3 domain of MCL-1 itself.

The helical BH3 domain of MCL-1 is located within a small "pocket" in the protein structure, and acts as a dock to enable binding of other proteins. It is by means of this docking unit that MCL-1 "traps" pro-death proteins and keeps them from triggering apoptosis in cancer cells. The scientists didn't expect to find that MCL-1's own BH3 domain could, when inserted into the pocket, inhibit its own pro-survival behavior.

"When we uncovered nature's
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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert  

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