5X4Q

Crystal structure of the BCL6 BTB domain in complex with Compound 7

Summary for 5X4Q

• Entry DOI: 10.2210/pdb5x4q/pdb
• Related: 5X4M 5X4N 5X4O 5X4P
• Descriptor: B-cell lymphoma 6 protein, 5-[[5-chloranyl-2-(pyridin-3-ylmethylamino)pyrimidin-4-yl]amino]-1,3-dihydroindol-2-one, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: transcription repressor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P41182
• Total number of polymer chains: 1
• Total formula weight: 16755.70

Authors

Sogabe, S.,Ida, K.,Lane, W.,Snell, G. (deposition date: 2017-02-13, release date: 2017-05-24, Last modification date: 2023-11-22)

Primary citation

Kamada, Y.,Sakai, N.,Sogabe, S.,Ida, K.,Oki, H.,Sakamoto, K.,Lane, W.,Snell, G.,Iida, M.,Imaeda, Y.,Sakamoto, J.,Matsui, J.
Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach
J. Med. Chem., 60:4358-4368, 2017

PubMed Abstract: 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 = 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 = 0.078 μM, LE = 0.37, cell-free protein-protein interaction (PPI) IC = 0.48 μM (ELISA), cellular PPI IC = 8.6 μM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.

PubMed: 28471657
DOI: 10.1021/acs.jmedchem.7b00313

Experimental method

X-RAY DIFFRACTION (2 Å)