Alex G. Waterson
Prior to joining Vanderbilt, I worked in the Oncology Medicinal Chemistry department at GlaxoSmithKline, where I contributed, among other projects, to the discovery of dabrafenib, a drug currently used to treat melanoma patients with a B-Raf mutation. Since coming to Vanderbilt in 2008, I have collaborated with several Vanderbilt faculty and have continued to explore my interest in applying synthetic and medicinal chemistry to questions of biological importance.
As a Research Assistant Professor of Pharmacology and Chemistry and a medicinal chemist in the Fesik lab for cancer drug discovery, I lead several fragment-based drug discovery efforts. Our lab seeks to link together multiple small fragment molecules that bind to a protein of interest to generate a much more potent inhibitor. Our work is heavily based on structural guidance from X-ray co-crystal structures of our compounds when bound to the protein of interest. Using medicinal chemistry principles, we optimize these linked inhibitors for activity in various biochemical and cellular assays to create lead molecules for continued drug discovery efforts. In order to accomplish this multi-disciplinary work, the Fesik lab has assembled a team of structural biologists, chemists, biochemists, and cell biologists, many of whom have significant prior experience in the pharmaceutical industry, and all of whom work together to drive our projects forward.
One active program in the lab has resulted in the discovery of multiple chemical series of potent inhibitors of Replication Protein A, a protein which is important in the initiation of the DNA damage response and repair pathways. We also have a major effort aimed at the inhibition of K-Ras, which sits at the intersection of several cellular signaling pathways and is one of the most frequently mutated proteins in human cancers. A drug discovery program aimed at inhibition of the apoptotic protein Mcl-1 is another major component of the research in our lab.
In another role at Vanderbilt, I am the Co-Principal Investigator of the Vanderbilt Chemical Diversity Center, an entry in the National Cancer Institute's Chemical Biology Consortium. In this work, the VCDC has contributed to three different cancer drug discovery programs, along with collaborators at multiple institutions around the country.
By virtue of my prior role as the Director of the Chemical Synthesis Core here at Vanderbilt, I maintain several successful collaborations with various Vanderbilt faculty, including an effort that has discovered molecules that restore the expression of E-cadherin and thus might reverse the mesenchymal phenotype that is one of the hallmarks of aggressive cancer cells. In another active collaboration, we have identified and optimized a series of insect odorant receptor agonists that may be useful as a mosquito repellent with a novel mechanism of action, and thus protect against malarial infection.