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A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.

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.

SUBMITTER: Cerchietti LC

PROVIDER: S-EPMC2858395 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.

Cerchietti Leandro C LC Ghetu Alexandru F AF Zhu Xiao X Da Silva Gustavo F GF Zhong Shijun S Matthews Marilyn M Bunting Karen L KL Polo Jose M JM Farès Christophe C Arrowsmith Cheryl H CH Yang Shao Ning SN Garcia Monica M Coop Andrew A Mackerell Alexander D AD Privé Gilbert G GG Melnick Ari A

Cancer cell 20100401 4

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 expres ...[more]

PMID: 20385364

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