6C3N

Crystal structure of BCL6 BTB domain in complex with compound 7CC5

6C3N の概要

• エントリーDOI: 10.2210/pdb6c3n/pdb
• 分子名称: B-cell lymphoma 6 protein, N-(2-phenylethyl)-N'-pyridin-3-ylthiourea (3 entities in total)
• 機能のキーワード: inhibitor, protein-protein interaction, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30347.32

構造登録者

Linhares, B.,Cheng, H.,Xue, F.,Cierpicki, T. (登録日: 2018-01-10, 公開日: 2019-01-16, 最終更新日: 2023-10-04)

主引用文献

Cheng, H.,Linhares, B.M.,Yu, W.,Cardenas, M.G.,Ai, Y.,Jiang, W.,Winkler, A.,Cohen, S.,Melnick, A.,MacKerell Jr., A.,Cierpicki, T.,Xue, F.
Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.
J.Med.Chem., 61:7573-7588, 2018

PubMed Abstract: Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6 has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to BCL6. From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X-ray crystallography has yielded an inhibitor, 15f, that demonstrated over 100-fold improved potency for BCL6. This gain in potency was achieved by a unique binding mode that mimics the binding mode of the corepressor SMRT in the aromatic and the HDCH sites. The structure-activity relationship based on these new inhibitors will have a significant impact on the rational design of novel BCL6 inhibitors, facilitating the identification of therapeutics for the treatment of BCL6-dependent tumors.

PubMed: 29969259
DOI: 10.1021/acs.jmedchem.8b00040

実験手法

X-RAY DIFFRACTION (2.53170577659 Å)