Adam M Thomas, Marta Serafini, Emma K Grant, Edward A J Coombs, Joseph P Bluck, Matthias Schiedel, Michael A McDonough, Jessica K Reynolds, Bernadette Lee, Michael Platt, Vassilena Sharlandjieva, Philip C Biggin, Fernanda Duarte, Thomas A Milne, Jacob T Bush, Stuart J Conway
Target validation remains a challenge in drug discovery, which leads to a high attrition rate in the drug discovery process, particularly in Phase II clinical trials. Consequently, new approaches to enhance target validation are valuable tools to improve the drug discovery process. Here, we report the combination of site-directed mutagenesis and electrophilic fragments to enable the rapid identification of small molecules that selectively inhibit the mutant protein. Using the bromodomain-containing protein BRD4 as an example, we employed a structure-based approach to identify the L94C mutation in the first bromodomain of BRD4 [BRD4(1)] as having a minimal effect on BRD4(1) function...
October 24, 2023: ACS Chemical Biology