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

• Published in: Journal of medicinal chemistry Vol. 60; no. 10; pp. 4358 - 4368
• Main Authors: Kamada, Yusuke, Sakai, Nozomu, Sogabe, Satoshi, Ida, Koh, Oki, Hideyuki, Sakamoto, Kotaro, Lane, Weston, Snell, Gyorgy, Iida, Motoo, Imaeda, Yasuhiro, Sakamoto, Junichi, Matsui, Junji
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.05.2017
• Subjects: Drug Discovery; Humans; Ligands; Molecular Docking Simulation; Protein Interaction Maps - drug effects; Proto-Oncogene Proteins c-bcl-6 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-6 - chemistry; Proto-Oncogene Proteins c-bcl-6 - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Surface Plasmon Resonance
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00313

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 K D = 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 K D = 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.