%0 Journal Article %A Kamada, Yusuke %A Sakai, Nozomu %A Sogabe, Satoshi %A Ida, Koh %A Oki, Hideyuki %A Sakamoto, Kotaro %A Lane, Weston %A Snell, Gyorgy %A Iida, Motoo %A Imaeda, Yasuhiro %A Sakamoto, Junichi %A Matsui, Junji %D 2017 %T Discovery of a B‑Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach %U 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 %R 10.1021/acs.jmedchem.7b00313.s001 %2 https://acs.figshare.com/ndownloader/files/8413025 %K compound 7 %K ligand BCoR peptide %K PPI IC 50 %K lymphocytes %K transcriptional factor %K structure-based design %K fragment 1 %K cancer treatment %K interaction %K 0.078 μ M %K high-throughput screening %K 8.6 μ M %K ELISA %K SPR K D %K Biophysics-Driven Fragment-Based Approach B-cell lymphoma 6 %K surface plasmon resonance %K IC 50 %K LE %K M 2H %K BCL 6 %K 0.48 μ M %K 1200 μ M %K ligand efficiency %K biophysics-driven fragment-based approach %X 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. %I ACS Publications