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

Journal Article · Wed Sep 22 00:00:00 EDT 2010 · Cancer Cell

DOI:https://doi.org/10.1016/j.ccr.2009.12.050· OSTI ID:1002718

Cerchietti, L C; Ghetu, A F; Zhu, X; Da Silva, G F; Zhong, S; Matthews, M; Bunting, K L; Polo, J M; Fares, C; Arrowsmith, C H; Yang, S N; Garcia, M; Coop, A; Mackerell, A D; Prive, G G; Melnick, A ^[1]

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1. Cornell

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1002718
• Journal Information: Cancer Cell, Vol. 17, Issue (4) ; 04, 2010
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
CRYSTALLOGRAPHY
DESIGN
FUNCTIONALS
GENES
IN VITRO
IN VIVO
LYMPHOMAS
NEOPLASMS
ONCOGENES
PATIENTS
TARGETS