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

Cancer Cell. 2010 Apr 13;17(4):400-11. doi: 10.1016/j.ccr.2009.12.050.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Protein Conformation
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / toxicity
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / toxicity
  • Transcription, Genetic
  • Zinc Fingers

Substances

  • BCOR protein, human
  • Proto-Oncogene Proteins
  • Repressor Proteins

Associated data

  • PDB/3LBZ