TitleIdentification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.
Publication TypeJournal Article
Year of Publication2018
AuthorsCheng, Huimin, Linhares Brian M., Yu Wenbo, Cardenas Mariano G., Ai Yong, Jiang Wenjuan, Winkler Alyssa, Cohen Sandra, Melnick Ari, MacKerell Alexander, Cierpicki Tomasz, and Xue Fengtian
JournalJ Med Chem
Date Published2018 Sep 13
KeywordsAntineoplastic Agents, BTB-POZ Domain, Cell Line, Tumor, Computer-Aided Design, Crystallography, X-Ray, Drug Design, Humans, Hydrogen Bonding, Lymphoma, Large B-Cell, Diffuse, Magnetic Resonance Spectroscopy, Proto-Oncogene Proteins c-bcl-6, Small Molecule Libraries, Structure-Activity Relationship, Thiourea

<p>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.</p>

Alternate JournalJ Med Chem
PubMed ID29969259
PubMed Central IDPMC6334293
Grant ListR44 GM109635 / GM / NIGMS NIH HHS / United States