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; Emma L. Rivers
ACS Med. Chem. Lett., 2024, XXXX, XXX, XXX-XXX
https://doi.org/10.1021/acsmedchemlett.4c00113

Abstract

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.