Research Abstract
The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Our goal is to create an arsenal of new compounds-a “chemical toolbox”-to investigate and block protein interactions that cause cancer. To achieve these objectives, we take a multidisciplinary approach that employs synthetic chemistry techniques, structural biology analyses, and biochemical, cellular, and mouse modeling experiments to systematically dissect the pathologic signaling pathways of interest.
We develop and apply new approaches to chemically stabilize natural peptides so that their shape, and therefore their anti-cancer activities can be restored. Optimizing natural peptides in this way provides alternative compounds to study protein interactions and manipulate biological pathways within cells to treat human disease. For example, we have used a chemical strategy, termed “hydrocarbon-stapling,” to synthesize a panel of pro-apoptotic peptides with markedly improved pharmacological properties. We have demonstrated that the stapled peptides retain their natural shape, are resistant to degradation, and can enter and kill leukemia cells by neutralizing their survival proteins. When administered to mice with leukemia, a stapled peptide modeled after the BH3 death domain of a BCL-2 family protein successfully blocked cancer growth and prolonged the lives of treated animals.
In ongoing studies, we broadly apply the new peptide-stapling strategy to produce a diversity of cancer biology discovery tools, in order to study and deactivate aberrant apoptotic and transcriptional pathways in a variety of human tumors. We emphasize the structural basis for ligand-protein interactions, validation of intracellular targets, characterization of novel protein interactors, analysis of ligand-mediated alteration of signaling pathways in cellular and murine models of disease, in vivo imaging technologies, and clinical translation.
