Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1
Simon C. C. Lucas, Alexander G. Milbradt, J. Henry Blackwell, Silvia Bonomo, Andrew S. Brierley, Doyle J. Cassar, Jared Freeman, Thomas E. Hadfield, Lucas A. Morrill, Rick Riemens, Sunil Sarda, Stefan Schießer, Daniel Wiktelius, Samiyah Ahmed, Mark J. Bostock, Ulf Börjesson, Claudia De Fusco, Carine Guérot, David Hargreaves, Sarah H. Hewitt, Michelle L. Lamb, Nancy Su, Ryan Whatling, Matthew L. Wheeler, Jason G. Kettle
Abstract
Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.