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 <b>1</b> (SPR <i>K</i><sub>D</sub> = 1200 μM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated <b>1</b> into the more potent compound <b>7</b> (SPR <i>K</i><sub>D</sub> = 0.078 μM, LE = 0.37, cell-free protein–protein interaction (PPI) IC<sub>50</sub> = 0.48 μM (ELISA), cellular PPI IC<sub>50</sub> = 8.6 μM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.