Professor William Pomerantz

Promotional Seminar
Professor William C. K. Pomerantz
Department of Chemistry
University Minnesota

Abstract

Organofluorine Chemistry at the Biological interface

Despite being the thirteenth most abundant element in the earth’s crust and most abundant halogen, fluorine remains largely absent from nature’s most essential biopolymers and natural products.  Despite this absence in biology, organofluorine compounds hold significant promise for impacting human health, including for imaging applications (¹⁸F PET and ¹⁹F MRI), structural biology, drug screening, and drug development. As one innovation in our lab, we develop protein-observed ¹⁹F NMR (PrOF NMR) approaches using ¹⁹F-labeled side-chains that are enriched at protein-protein-interaction interfaces. We use PrOF NMR for characterizing protein-protein and nucleic acid interactions and drug discovery applications.

Today, I will discuss one recent medicinal chemistry application of PrOF NMR, which has led to potent inhibitors and the first synthetic degraders (PROTACs) of the Bromodomain PHD Finger Transcription Factor, BPTF. BPTF has become increasingly identified as a pro-tumorigenic factor prompting investigations into the molecular mechanisms associated with BPTF function. Despite a druggable bromodomain which engages in protein-protein interactions with acetylated histones, small molecule discovery is at an early stage. Our lab has developed novel screening approaches using PrOF NMR, protein crystallography, and supporting biophysical methods to develop both the first inhibitor of the BPTF bromodomain, and now more potent and selective chemical probes. These molecules have been used in both cell-based assays and in vivo. They have demonstrated the importance of the bromodomain for mediating transcription as well as serving as a mechanism for reducing c-Myc occupancy on chromatin. Most recently they have showed synergistic effects with chemotherapeutic drugs in breast cancer models. Finally, their potential as novel heterobifunctional molecules will also be discussed.  These new inhibitors and degrader are envisioned to serve as useful chemical probes of BPTF function both in normal and pathophysiology. Time permitting, many of the enjoyable collaborations here at UMN will be briefly mentioned including work in ¹⁹F MRI, epigenetics, and environmental fate studies.

This talk will describe several case studies where PrOF NMR has been applied for fragment screening, ligand deconstruction, and screening of protein mixtures to develop inhibitors of epigenetic complexes.  New applications towards large and multi-domain proteins will also be highlighted.

William Pomerantz

William C. K. Pomerantz, Associate Professor of Chemistry, University of Minnesota. Prof. Pomerantz received his B.S. in chemistry from Ithaca College in 2002, followed by a Fulbright Fellowship at ETH, Zurich with Professors François Diederich and Jack Dunitz. He obtained a Ph.D. in chemistry under Professors Sam Gellman and Nick Abbott at the University of Wisconsin-Madison and was an NIH postdoctoral fellow under Prof. Anna Mapp at the University of Michigan. He joined the chemistry faculty at the University of Minnesota in 2012. He is a recent McKnight Presidential Fellow and current Merck Professor of chemistry.  His research focus is on developing chemical biology and medicinal chemistry approaches to modulate protein-protein interactions. Protein-Observed Fluorine NMR (PrOF NMR) is one such tool in his lab that is being developed for fragment-based drug discovery, and has been applied towards inhibiting epigenetic protein complexes.  Additional interests include macrocyclic peptide design, fluorinated imaging agents and sensors, and environmental fate studies of polyfluorinated molecules known as PFAS. He has published this research in over 70 peer reviewed research articles.  Aspects of his work have been recognized through an NSF CAREER award, Sidney Kimmel Cancer Scholar award, and a Rising Star in Chemical Biology award. Prof. Pomerantz is currently the global council co-chair for the International Chemical Biology Society and vice chair for the Early Career Board Member for ACS Med. Chem. Lett.