Identification of Thiourea-Based Inhibitors of the B‑Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design

Protein–protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6BTB has remained challenging. Usi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-09, Vol.61 (17), p.7573-7588
Main Authors: Cheng, Huimin, Linhares, Brian M, Yu, Wenbo, Cardenas, Mariano G, Ai, Yong, Jiang, Wenjuan, Winkler, Alyssa, Cohen, Sandra, Melnick, Ari, MacKerell, Alexander, Cierpicki, Tomasz, Xue, Fengtian
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
BTB-POZ Domain
Cell Line, Tumor
Computer-Aided Design
Crystal structure
Crystallography, X-Ray
Drug Design
electron correlation
functional groups
Humans
Hydrogen Bonding
indoles
inhibitors
Lymphoma, Large B-Cell, Diffuse - drug therapy
Lymphoma, Large B-Cell, Diffuse - pathology
Magnetic Resonance Spectroscopy
Proto-Oncogene Proteins c-bcl-6 - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-6 - chemistry
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Thiourea - chemistry
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Summary:Protein–protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6BTB 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 BCL6BTB. 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 BCL6BTB. 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00040