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

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posted on 04.05.2017 by Yusuke Kamada, Nozomu Sakai, Satoshi Sogabe, Koh Ida, Hideyuki Oki, Kotaro Sakamoto, Weston Lane, Gyorgy Snell, Motoo Iida, Yasuhiro Imaeda, Junichi Sakamoto, Junji Matsui
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.