A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

SummaryThe BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.

► We identified a specific BCL6 small-molecule inhibitor ► This compound targets the interaction of BCL6 with its corepressors ► This compound displayed antilymphoma activity in vitro and in vivo