The transcription factor B-cell lymphoma 6 (BCL6) has been identified as a driver of oncogenesis in lymphoid malignancies. BCL6 is implicated in several protein-protein interactions with corepressors, and disruption of these interactions are currently being investigated as a strategy for cancer treatment. A range of small molecules that target BCL6 have been reported, including reversible inhibitors such as compound 11 (GSK137), and macrocyclic compound 12. Compounds with alternative mechanisms have also been reported, including degraders such as compound 13 (BI-3802), and more recently, rationally designed covalent inhibitor 14 (TMX-2164) that targets Tyr57 (Fig. &). The top hits from the SF screen with BCL6 represented two distinct chemotypes: meta-substituted benzamides (2f and 2g) and azetidine aryl ethers (2h and 2i). These were resynthesised and purified for follow-up studies. Tandem MS was used to identify the amino acid residue(s) responsible for covalent modification, and interestingly, the two different chemotypes were found to target two different residues (Fig. &). The results showed that meta-substituted benzamides 2f (373 Da) and 2g (344 Da) modified Tyr57 on the peptide 47TVLMACSGLFY*SIFTDQLKR66, and azetidine aryl ethers 2h (365 Da) and 2i (372 Da) modified His115 on the 98EGNIMAVMATAMYLQMEH*VVDTCR121 (see Fig. ). Tyr57 has previously been targeted by a BCL6 inhibitor (14, TMX-2164), however, the targeting of His115 is a novel modification; these residues are located on opposite sides of the binding site of previously reported BCL6 inhibitors (11-14) (see Fig. ).