The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. To achieve our 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 have developed and applied “stapled peptides” that preserve the structure of biologically-active peptides as new chemical probes and prototype therapeutics tointerrogate the BCL-2 family-regulated mitochondrial apoptosis pathway. For example, we identified the elusive trigger site on pro-apoptotic BAX that mediates its direct activation by activator BH3-only proteins, generated full-length BAK for the first time and characterized its direct activation mechanism, and discovered that one of the most potent and selective inhibitors of anti-apoptotic MCL-1 is its own BH3-interaction domain. Most recently, we found that the BH4 domain helix of BCL-2 can independently block pro-apoptotic BAX activation by targeting BAX at a novel interaction site. By interrogating BCL-2 family signaling proteins using a diversity of analytical approaches, we aim to uncover the interaction surfaces and mechanisms that regulate apoptotic function. We strive to conduct structure-function studies that will advance our fundamental understanding of these oncogenic proteins so that new therapeutic strategies can be developed to overcome cancer chemoresistance.
We have also developed stapled peptides to investigate a variety of other targets in cancer, including HDM2/HDMX for p53 reactivation, β-catenin for blocking pathologic Wnt signaling, and EED for inhibiting the PRC2 epigenetic regulatory complex. On the exploratory front, we have harnessed stapled peptides to expand our grasp of the α-helical interactome. For example, we developed a photoaffinity labeling and mass spectrometry method that leverages photoreactive stapled peptides to identify novel protein targets and their explicit sites of interaction. This has led to rapid identification of novel protein surfaces amenable to therapeutic targeting in cancer and diabetes. In addition, we have applied our chemical approach to reinforcing bioactive structures to develop anti-viral fusion inhibitors and, most recently, structured antigens for experimental vaccines.
The overarching goals of the Walensky laboratory are to (1) operate at the interface of chemistry, biology, biotechnology, and translational medicine to drive fundamental basic science discovery, (2) provide a vibrant and multidisciplinary laboratory environment for postdoctoral and graduate training, and (3) maintain laser focus on harnessing the fresh scientific insights and trainee talent to advance new treatments for our patients.