In this work, we compared a structure-based design approach starting from a known KAc-mimic moiety, to screening a library of diverse covalent fragments. While the former can be exploited for proteins with known binding ligands, as in the case of BRD4, the second could potentially afford a strategy to identify ligands for a target for which none currently exist. This approach allowed us to discover, without the need of extensive SAR studies, a ligand that selectively binds to BRD4(1) over BRD4 (2). This 'mutate and conjugate' approach has the potential to provide a general strategy for rapidly identifying covalent ligands to assist in the target validation of a protein of interest.