Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Cell Rep. 2017 Sep 19;20(12):2860-2875. doi: 10.1016/j.celrep.2017.08.081.


The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

Keywords: BTB domain; cancer; drug discovery; drug target; lymphoma; oncogene; transcription factor; ubiquitin.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / drug effects
  • Protein Domains
  • Proteolysis* / drug effects
  • Proto-Oncogene Proteins c-bcl-6 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-6 / chemistry
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Ubiquitination / drug effects


  • Proto-Oncogene Proteins c-bcl-6
  • Pyrimidines
  • DNA
  • Proteasome Endopeptidase Complex