The SF fragment screen also identified novel hits for BCL6, a therapeutic target under investigation for conditions such as blood, breast, and lung cancers. Interestingly, the screen afforded two hit series that were found to covalently modify residues on opposite sides of the same pocket, one to a tyrosine and one to a histidine, highlighting the versatility of the approach in targeting nucleophilic amino acid residues within a binding pocket. In this case, the pool of hit compounds was rapidly expanded upon by an iterative screen, and the hits represented the two novel chemotypes for BCL6. The attenuation of covalent modification when incubated in the presence of GSK137, a published BCL6 inhibitor, implied that the fragments target a known small-molecule binding surface. Co-crystal structures of BCL6 with hit SFs were obtained, which confirmed that the binding conformations overlapped with that of GSK137, positing the fragment as a covalent probe to aid the discovery of novel inhibitors of the BCL6 BTB/POZ domain.