Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 (BCL6) BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design

摘要

Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6^BTB) and its co-repressors have emerged as a promising target for anti-cancer therapeutics. However, identification of potent, drug-like inhibitors of the BCL6^BTB 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 the BCL6^BTB. From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X-ray crystallography has yielded an inhibitor >15f, which demonstrated over 100-fold improved potency for the BCL6^BTB. This gain in potency was achieved by a unique binding mode that mimics the binding mode of the corepressor SMRT into 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.