6CQ1

BCL6 BTB domain in complex with 15a

Summary for 6CQ1

• Entry DOI: 10.2210/pdb6cq1/pdb
• Descriptor: B-cell lymphoma 6 protein, 2-{6-({[2-(1H-indol-3-yl)ethyl]carbamothioyl}amino)-3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-1-yl}-N-(propan-2-yl)acetamide (3 entities in total)
• Functional Keywords: protein protein inhibitor, protein binding, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 30924.10

Authors

Linhares, B.M.,Cheng, H.,Xue, F.,Cierpicki, T. (deposition date: 2018-03-14, release date: 2019-03-20, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.69921037793 Å)