5X4O

Crystal structure of the BCL6 BTB domain in complex with Compound 5

5X4O の概要

• エントリーDOI: 10.2210/pdb5x4o/pdb
• 関連するPDBエントリー: 5X4M 5X4N 5X4P 5X4Q
• 分子名称: B-cell lymphoma 6 protein, N-methyl-N-{3-[({2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}methanesulfonamide (3 entities in total)
• 機能のキーワード: transcription repressor, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P41182
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16795.22

構造登録者

Sogabe, S.,Ida, K.,Lane, W.,Snell, G. (登録日: 2017-02-13, 公開日: 2017-05-24, 最終更新日: 2023-11-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.05 Å)