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

Cerchietti , Leandro C.; Ghetu , Alexandru F.; Zhu, Xiao; Da Silva , Gustavo F.; Zhong, Shijun; Matthews , Marylin; Bunting , Karen L.; Polo, Jose M.; Farès, Christophe; Arrowsmith, Cheryl H.; Ning Yang, Shao; Garcia, Monica; Coop, Andrew; MacKerell Jr. , Alexander D.; Privé , Gilbert G.; Melnick, Ari

doi:10.1016/j.ccr.2009.12.050

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

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Cerchietti, L. C., Ghetu, A. F., Zhu, X., Da Silva, G. F., Zhong, S., Matthews, M., et al. (2010). A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo. Cancer Cell, 17(4), 400-411. doi:10.1016/j.ccr.2009.12.050.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-4601-4

Abstract

The 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.