Our Mission

Effective cancer treatment still remains one of the most critical unmet medical needs. Despite many years of research, we do not have effective drugs for this formidable disease that affects almost everyone in one way or another. However, this will soon change. We have learned a lot about the causes of cancer and the proteins that we need to target to discover new and improved cancer drugs. In addition, we have developed the technologies to drug these highly validated targets. Finally, we now have methods to diagnose cancers based on the genetics of an individual’s disease and will eventually be able to treat these individuals with drugs tailored for their particular disease. This is exciting times in cancer research. Our mission is to discover drugs to treat cancer that will effectively shrink tumors and lead to cures. We have chosen to target proteins that make outstanding cancer targets but are technically challenging to drug. To tackle such difficult targets, we  rely heavily on state-of-the-art methodologies such as fragment-based methods and structure-based design.

Fragment-Based Drug Discovery

The traditional approach to drug design involves the screening of a library of relatively large, intact compounds against the desired protein target. These target proteins have “pockets” to which drugs bind and can interfere with their activity. Our chemists try to find a molecule that will fit best into these pockets and affect the protein’s activity.

To find such molecules, we screen for fragments or pieces of a  molecule that bind to subpockets of a binding site and then link them together, like Tinkertoys. Once our fragment-based screen identifies chemical fragments that bind to “subpockets” on the target protein’s binding surface, the 3-dimensional structure of the protein bound to the drug fragments is determined with NMR spectroscopy or X-ray crystallography. The 3-dimensional structures provide a picture of how the fragments fit into the protein’s binding site – and how they might be linked together. The fragments can then be assembled into a larger molecule that better fills up the target protein’s binding pocket. This can be accomplished by fragment linking, fragment growing, and fragment merging. It’s a modular approach to drug discovery.

The fragment-based approach has several advantages over conventional methods and is ideal for identifying leads for technically challenging protein targets such as the ones we have chosen to target. Hits can be found in a fragment-based screen that cannot be found by conventional high throughput screening of large libraries of complex molecules. This is due to the difference in the stringencies in the screens.

Our Facilities and Resources

Please read about our lab facilities and resources available to us at Vanderbilt University on the Facilities page.