09/19/17 - 9:45 AM to 11:00 AM
Department Seminar: Professor William C.K. Pomerantz
"Inspiration from Fluorination: Chemical Biology Approaches to Probe Molecular Recognition Events in Transcription"
My research program seeks to understand the atomic-level details of protein-protein interactions (PPIs) with a focus on improving our knowledge of macromolecular recognition events. The impact of such findings will aid development of new medicines to significantly improve human health. Using 19F NMR, our unique contribution to this challenging field is our ability to develop new synthetic molecules, either small molecule, nanoparticle, or peptide-based to both image and disrupt harmful PPI signaling events.
Protein-protein interaction inhibitor discovery has proven difficult due to the large surface area and dynamic interfaces of proteins. To facilitate the early lead discovery rate, I will first describe a rapid protein-based 19F NMR method for detecting protein-ligand interactions by screening low complexity molecules (fragments) as well as higher complexity molecules. We label the aromatic amino acids with the highly sensitive fluorine atom, due to the high conservation of aromatic residues at protein interfaces. We have tested the sensitivity, accuracy, and speed of this method with the protein interaction domain of CBP, KIX, screening 508 small molecule fragments. In the second part of the talk, I will describe improvements in our method for the field of epigenetics targeting bromodomain-containing proteins Brd4, BrdT and BPTF. These studies have led to the discovery of some of the first selective ligands for the bromodomain BPTF and new submicromolar ligands for Brd4. Finally, I will address the synthesis, development, and application of two of our new chemical probes for studying epigenetic protein function, including a new role for BPTF regulation of the oncogene, c-Myc. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands for bromodomains and may find utility in the study of additional epigenetic “reader” domains.
Professor Pomerantz is an assistant professor and McKnight Land-Grant Professor in the Department of Chemistry. He has been a professor in the Department of Chemistry since 2012. He also is an affiliate faculty member in the Department of Medicinal Chemistry and one of the founding members of the Epigenetics Consortium on campus. Before coming to the University of Minnesota, he was a National Institutes of Health post-doctoral research fellow at the University of Michigan. He earned his doctorate in organic chemistry from the University of Wisconsin-Madison, spent a year as a Seydel/Fulbright Fellow at the Swiss Federal Institute of Technology in Zurich, Switzerland, and earned his bachelor’s degree in chemistry from Ithaca College. His honors and awards include being named a Cottrell Scholar by the Research Corporation for Science Advancement, receiving a Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research, and receiving a National Science Foundation CAREER award.