News Release

Two Scientists From The Scripps Research Institute Receive Funding for New Approach to Breast Cancer Research

La Jolla, CA. July 9, 2002 - Two scientists at The Scripps Research Institute (TSRI) were recently awarded seed funding from the California Breast Cancer Research Program for design of breast cancer drugs. The award is part of a pool of state money earmarked for breast cancer and set aside to fund innovative research that has the potential to have a high impact.

Assistant Professor Flavio Grynszpan, Ph.D., and Associate Professor Vito Quaranta, M.D., plan to use the $136,000 to develop inhibitors of proteins that belong to a family of enzymes called matrix metalloproteinases, which are known to be responsible for the invasive properties of breast cancer cells. They plan to use a technology called "click chemistry" that was developed at TSRI to design these inhibitors.

Metalloproteinases belong to a broad category of essential enzymes that are involved in a number of normal physiological processes. Certain metalloproteinases have long been a target for breast cancer therapy, since inhibiting them prevents cancerous cells from invading surrounding tissues and contains breast cancer. And, indeed, drugs have been developed and tested to block metalloproteinases in the past.

However, these past drugs failed in clinical trials because they had side effects such as intolerable joint pain and toxicity.

"We are going to apply a new technology, recruiting the help of the actual enzyme target to develop selective inhibitors - ones that will not hit other matrix metalloproteinases," says Grynszpan.

This technology, click chemistry, was envisioned and developed by TSRI Professor and 2001 Nobel laureate in Chemistry K. Barry Sharpless, Ph.D., who is also a collaborator on this project. The approach relies on efficient irreversible reactions between "spring-loaded" building blocks and provides ready access to diverse libraries of small molecules that can be developed successfully into drugs.

More importantly, unlike other drug discovery methods, click chemistry can mobilize the target enzyme itself, an MMP in this case, to play a decisive role in selecting and connecting the pieces generating the right inhibitor.

The building blocks can be chosen for their ability to fit snugly into one side or the other of the metalloproteinase "active site," which is where the final inhibitor binds. Occasionally, the enzyme will accelerate the reaction between certain building blocks, forming a compound that better binds to the "active site." In the absence of the enzyme, that product formation would be negligible.

The metalloproteinase, then, acts as the reaction vessel for the formation of its own inhibitor, which can then be isolated, tested, and developed as a drug candidate.

The feasibility of this approach was demonstrated recently in the discovery of the best known inhibitor for the enzyme acetylcholinesterase, an important nerve junction enzyme involved in regulating transmission of nerve impulses.

For more information on the technique, see the research article "Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks," authored by Warren G. Lewis, Luke G. Green, Flavio Grynszpan, Zoran Radic, Paul R.Carlier, Palmer Taylor, M.G. Finn, and K. Barry Sharpless, which appeared in the March 15, 2002 issue of Angewandte Chemie or see:

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