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

作者：Cerchietti Leandro C; Ghetu Alexandru F; Zhu Xiao; Da Silva Gustavo F; Zhong Shijun; Matthews Marilyn; Bunting Karen L; Polo Jose M; Fares Christophe; Arrowsmith Cheryl H; Yang Shao Ning; Garcia Monica; Coop Andrew; MacKerell Alexander D Jr^*; Prive Gilbert G; Melnick Ari

来源：Cancer Cell, 2010, 17(4): 400-411.

DOI：10.1016/j.ccr.2009.12.050

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 BIB 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.

• 出版日期2010-4-13