Discovery of Reversible Covalent Binders to Bfl-1 using DNA-Encoded Chemical Libraries
DNA-encoded chemical library (DEL) technology enables the efficient screening of large collections of encoded compounds and has emerged as a powerful tool for hit identification. A DEL screen against Bfl-1 (Bcl-2-related protein A1) identified the first known reversible covalent small-molecule ligand for Bfl-1, an oncogenic protein that is overexpressed in both hematological and solid tumors. The binding of the cyano-acrylamide DEL compound was validated through biophysical and biochemical techniques. A 10-fold improvement in potency was achieved through SAR exploration and resulted in an analogue that was successfully cocrystallized in Bfl-1, confirming its covalent interaction with Cys55.
This poster is presented at the 2024 Discovery on Target Conference
