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

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.