Simon C. C. Lucas, J. Henry Blackwell, Ulf Börjesson, David Hargreaves, Alexander G. Milbradt, Samiyah Ahmed, Mark J. Bostock, Carine Guerot, Andrea Gohlke, Olaf Kinzel, Michelle L. Lamb, Nidhal Selmi, Christopher J. Stubbs, Nancy Su, Qibin Su, Haiou Luo, Ting Xiong, Xiaoqian Zuo, Sana Bazzaz, Corey Bienstock, Paolo A. Centrella, Kyle E. Denton, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher Hupp, Anthony D. Keefe, Takashi Satoh, Ying Zhang, and Emma L. Rivers
ACS Medicinal Chemistry Letters 2024
DOI: 10.1021/acsmedchemlett.4c00113
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are 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 cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
