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Drugs that inhibit a protein’s function do so by binding that protein and blocking interfaces relevant to its activity. This requires drugs to have high affinities towards and to be in high excess of their targets. Another approach called Proteolysis targeting chimeras (PROTACs) can be used, which hijacks a cell’s protein-degradation pathway by linking an E3-ligase to a target protein, leading to that protein’s degradation. To date, PROTACs molecules only utilize a handful of the over 600 potential E3 ligase handles and this limits PROTAC developmental potential. To address this, we propose a ligand discovery project for the E3 ligase scaffolds of BTRC and FBXW11. Using purified proteins, we will preform biophysical assays to screen libraries of small-molecules for ligands that interact with BTRC and FBXW11. Using structural biology techniques, we will solve the atomic structures of lead protein-ligand interactors to enable rational drug design in the future.
Cheryl Arrowsmith
Danton Ivanochko
Boehringer Ingelheim RCV GmbH & Co KG
Medicine
Manufacturing
University of Toronto
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