Casey Krusemark

Purdue University

Hosted by: Dr. Venditti

Title:

Exploiting Proximity-Induced Reactions for DNA-encoded Library Assays and Covalent Inhibitors

Abstract:

Proximity-induced reactions are powerful tools that can benefit both drug discovery efforts and increase drug potency through covalent trapping. DNA-encoded chemical libraries (DELs) have emerged as a new tool for de novo discovery of protein ligands. We have developed an affinity labeling approach to an in vitro selection assay that facilitates ligand discovery from DELs. Covalent crosslinking has significant benefits for targeting proteins in crude cell lysates, inside live cells, and the exterior of live cells. We present an evaluation of these assays to target proteins, specifically opioid receptor GPCRs. Additionally, we present the use of cyclic imine Mannich electrophiles to create targeted covalent inhibitors through reactions with tyrosine side chains. We evaluate the intrinsic reactivity of several Mannich electrophiles for reactivity to electron-rich aromatic groups. Using a DEL-derived inhibitor of the CBX8 chromodomain, we create covalent inhibitors and evaluate their efficacy in cell culture.