Kamada, Yusuke Sakai, Nozomu Sogabe, Satoshi Ida, Koh Oki, Hideyuki Sakamoto, Kotaro Lane, Weston Snell, Gyorgy Iida, Motoo Imaeda, Yasuhiro Sakamoto, Junichi Matsui, Junji 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. 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 2017-05-04
    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
10.1021/acs.jmedchem.7b00313.s001