Author/Authors :
Cerchietti، نويسنده , , Leandro C. and Ghetu، نويسنده , , Alexandru F. and Zhu، نويسنده , , Xiao and Da Silva، نويسنده , , Gustavo F. and Zhong، نويسنده , , Shijun and Matthews، نويسنده , , Marilyn and Bunting، نويسنده , , Karen L. and Polo، نويسنده , , Jose M. and Farès، نويسنده , , Christophe and Arrowsmith، نويسنده , , Cheryl H. and Yang، نويسنده , , Shao Ning and Garcia، نويسنده , , Monica and Coop، نويسنده , , Andrew and MacKerell Jr.، نويسنده , , Alexander D. and Privé، نويسنده , , Gilbert G. and Melnick، نويسنده , , Ari، نويسنده ,
Abstract :
Summary
L6 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.
