Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

J Med Chem. 2017 May 25;60(10):4358-4368. doi: 10.1021/acs.jmedchem.7b00313. Epub 2017 May 11.


B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR KD = 1200 μM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR KD = 0.078 μM, LE = 0.37, cell-free protein-protein interaction (PPI) IC50 = 0.48 μM (ELISA), cellular PPI IC50 = 8.6 μM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Drug Discovery
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Protein Interaction Maps / drug effects*
  • Proto-Oncogene Proteins c-bcl-6 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-6 / chemistry
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Surface Plasmon Resonance


  • BCL6 protein, human
  • Ligands
  • Proto-Oncogene Proteins c-bcl-6
  • Small Molecule Libraries