Identification, Evaluation and Optimization of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen
Bfl-1 is over-expressed in both hematological and solid tumors, inhibitors of Bfl-1 are therefore highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible-covalent small molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible-covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible-covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully co-crystallized in Bfl-1 revealing the binding-mode and providing further evidence of a covalent interaction with Cys55.