This Seminar will host Dr Dafydd Owen, Senior Scientific Director at Pfizer Medicine Design and our own Dr Fangyuan Cao (ICL).
Agenda
13:30 – 14:00 Dr Fangyuan Cao (Imperial College London)
Discovery of a potent deubiquitinase small molecule activity-based probe
Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, which can lead to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many disease states, including cancer, neurodegeneration and inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin-derived covalent activity-based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling we identify a novel cyanopyrrolidine (CNPy) probe IMP-2373 as a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cell systems. Through proteomics and targeted assays, we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs in diverse cell lines across a range of non-toxic concentrations. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition, and during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes.
14:00 – 15:00 Main speaker: Dafydd Owen (Pfizer): The Discovery of PAXLOVID
Structural insight on the SARS-CoV-2 Mpro and previous small molecule experience with intravenous SARS-CoV-1 inhibitors gave a starting point for an oral Mpro inhibitor program in response to the COVID-19 outbreak in March 2020. Working in a peptidomimetic chemotype, the team investigated a number of cysteine traps in reversibly covalent inhibitors, while looking to confer sufficient metabolic stability and permeability to attain oral bioavailability. This work resulted in the discovery of nirmatrelvir, the first oral SARS-CoV-2 Mpro inhibitor to reach clinical development. Nirmatrelvir/ritonavir went on to receive emergency use authorization for the treatment of high risk COVID-19 patients in the United States as PAXLOVID in December of 2021, just 17 months after nirmatrelvir was first synthesized.
Short Bio
Dafydd Owen has twenty-three years of experience as a medicinal chemist in the design and synthesis of drug-like molecules for Pfizer at its Sandwich UK and Cambridge MA research sites. He obtained his first degree at Imperial College in 1994 before moving to the University of Cambridge to gain a Ph.D under the supervision of Professor Steve Ley in 1997. Having won a research fellowship for postdoctoral work, he spent 1998 with Professor Leo Paquette at Ohio State University. During his research career he has delivered over one hundred invited lectures and is an author on over seventy research papers and patents. He has made contributions seven clinical candidates during his career at Pfizer. He serves as a board member of the Structural Genomics Consortium and sits on the editorial advisory board of the Journal of Medicinal Chemistry. He currently works in an outward looking, academically collaborative group for Pfizer looking to better understand protein families and their role in human disease through chemistry.
Most recently he led Pfizer’s oral protease inhibitor program that ultimately delivered PAXLOVID, the world’s first oral anti-viral therapy for the treatment of COVID-19.