Over the past several years a strong link between inflammation and multiple types of cancer has become apparent. The normal inflammatory response is the body's means of healing wounds and infections. This is accomplished by encouraging the growth of injured cells and by the formation of new blood vessels to bring cells from elsewhere in the body to help with the healing process. Cancer cells have usurped this normal process to provide themselves with hormones and an increased blood supply to stimulate their own growth. Two proteins, C/EBPa and NF-kB, often regulate the genes responsible for the inflammatory response. A key goal of our project is to identify small molecules that prevent interaction between C/EBPa and NF-kB. Our expectation is that such molecules would be useful in the therapy of a variety of cancers by inhibiting their ability to induce inflammation.

We are embarking on two strategies to identify the desired small molecules. The first approach involves obtaining the precise 3-dimensional structure of C/EBP bound to NF-kB. Using funds provided by the Waxman Foundation, I have recruited a post-doctoral fellow to my laboratory with extensive experience in obtained such structural information. In the several months that Dr. Ghosal has been in my laboratory, he has made nice progress towards the initial goal of purifying large quantities of C/EBPa and NF-kB from bacteria engineered to express these proteins. The next step will be to identify conditions that allow these proteins to form crystals and to then use X-rays to visualize these crystals and identify the location of each atom. With that information in hand, we will use computer-based drug design to identify candidate agents to be synthesized and tested. Our second strategy will involve a high-throughput screen in which thousands of known compounds are tested using a robotic system for their ability to inhibit interaction between C/EBPa and NF-kB. In addition, we are developing mouse models of acute leukemia that will be useful for testing the effectiveness of candidate agents.

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