Discovery of a B‑Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach Yusuke Kamada Nozomu Sakai Satoshi Sogabe Koh Ida Hideyuki Oki Kotaro Sakamoto Weston Lane Gyorgy Snell Motoo Iida Yasuhiro Imaeda Junichi Sakamoto Junji Matsui 10.1021/acs.jmedchem.7b00313.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_B_Cell_Lymphoma_6_Protein_Protein_Interaction_Inhibitor_by_a_Biophysics-Driven_Fragment-Based_Approach/4996712 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. 2017-05-04 00:00:00 compound 7 ligand BCoR peptide PPI IC 50 lymphocytes transcriptional factor structure-based design fragment 1 cancer treatment interaction 0.078 μ M high-throughput screening 8.6 μ M ELISA SPR K D Biophysics-Driven Fragment-Based Approach B-cell lymphoma 6 surface plasmon resonance IC 50 LE M 2H BCL 6 0.48 μ M 1200 μ M ligand efficiency biophysics-driven fragment-based approach