Alessio Ciulli holds the Personal Chair of Chemical Structural Biology at the School of Life Sciences, University of Dundee. Dr Ciulli’s laboratory has made important contributions to selective chemical intervention on protein-protein interactions targets and to the development of proteolysis-targeting chimeric molecules (PROTACs) as a viable strategy for targeted protein degradation. Amongst his most significant discoveries are the fragment-based design of ligands for the E3 ligase von Hippel-Lindau (VHL), and their use to design one of the first VHL-based PROTACs: the BET degrader MZ1. Dr Ciulli’s Lab later illuminated fundamental insights into PROTACs’ mechanism of action, solving the first crystal structure of a PROTAC ternary complex. Dr. Ciulli is also the scientific founder of Amphista therapeutics, a company that develops new protein degradation platforms.
Before joining Dundee, Dr Ciulli was a group leader at the University of Cambridge, where he previously earned his PhD degree. Amongst his honours are the EFMC Prize for Young Medicinal Chemist in Academia, the RSC Capps Green Zomaya Award in medicinal computational chemistry, and election as Fellow of the Royal Society of Chemistry.
How PROTAC degraders work and why the ternary complex matters
Degrader molecules (also known as PROTACs) recruit proteins to E3 ubiquitin ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the ligase and the target leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation.
In 2015, we disclosed MZ1, a potent BRD4 degrader made of our fragment-based designed VHL ligand, and a pan-BET inhibitor. Since then, my Lab has illuminated fundamental structural and biophysical understanding of PROTAC molecular recognition and mechanism of action, including solving the first crystal structure of a PROTAC ternary complex showing how MZ1 brings together VHL and its target protein BRD4. These fundamental insights into the mode of action provide guiding principles to rationally design degraders and other proximity-inducer modalities for translation chemical biology and drug discovery.
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