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

Yusuke KamadaNozomu SakaiSatoshi SogabeKoh IdaHideyuki OkiKotaro SakamotoWeston LaneGyorgy SnellMotoo IidaYasuhiro ImaedaJunichi SakamotoJunji Matsui
Published in: Journal of medicinal chemistry (2017)
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.
Keyphrases
  • protein protein
  • small molecule
  • cell free
  • diffuse large b cell lymphoma
  • peripheral blood
  • signaling pathway
  • gene expression
  • transcription factor
  • high throughput
  • single cell