How protein degraders work: Molecular mechanism and drug design
June 17, 2024 @ 13:00 – 14:00 CEST
Alessio Ciulli
Professor of Chemical Structural Biology
Founder and Director, Centre for Targeted Protein Degradation
School of Life Sciences, University of Dundee
Abstract
Protein degraders (also known as PROTACs and molecular glues) are a new class of small molecule tools and drugs that trigger the rapid depletion of a target protein inside the cell. Degraders work via forming a ternary complex, bridging a target protein to a ubiquitin E3 ligase. This allows the E3 ligase to label the target protein with ubiquitin molecules, leading to the protein being recognized and degraded by the proteasome. Whereas conventional drugs only inhibit disease-causing proteins by binding and locking up their most important functional parts for the duration of the drug’s action, degraders can bind at any positions and cause the protein rapid and long-lasting destruction. This lecture will recount some of our fundamental discoveries and insights that have helped to advance understanding and illuminate the molecular mechanism of how degraders work. It will illustrate how such fundamental principles have been applied to design high-quality degraders against challenging drug targets, and will highlight some of the latest progress from the laboratory.
Biography
Alessio Ciulli studied chemistry in Florence, Italy, and obtained his PhD from the University of Cambridge, UK, in 2006. After postdoctoral research in Cambridge and a brief visit at Yale University in the USA, he returned to Cambridge in 2009 to start his independent laboratory. In 2013, he moved to the University of Dundee, UK, where he was promoted to full professor in 2016. He has received numerous prizes and awards for his discoveries, most recently the 2022 Prous Institute – Overton and Meyer Award for New Technologies in Drug Discovery from the European Federation of Medicinal Chemistry (EFMC). In 2023 he was elected Fellow of the Royal Society of Edinburgh. He is the scientific founder of Amphista therapeutics, a targeted protein degradation company spin out of his laboratory, and the founder and director of the University of Dundee’s new Centre for Targeted Protein Degradation which opened in January 2023. The Ciulli Laboratory focuses on chemical biology and structural biology to develop small molecules inducing targeted protein degradation and modulating protein-protein interactions and translates their fundamental research via collaboration partnership with the biopharma industry and by creation of spin-out companies.
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