Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 that uses a sulfonyl fluoride to covalently react with the hydroxyl group of Tyrosine 58 located in the lateral groove. TMX-2164 exhibits significantly improved inhibitory activity compared to that of its reversible parental compound and displays sustained target engagement and antiproliferative activity in cells. TMX-2164 therefore represents an example of a tyrosine-directed covalent inhibitor of BCL6 which demonstrates advantages relative to reversible targeting.