6c3l

Publication Abstract from PubMed

Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6(BTB)) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of 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 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, that demonstrated over 100-fold improved potency for BCL6(BTB). 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.

Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.,Cheng H, Linhares BM, Yu W, Cardenas MG, Ai Y, Jiang W, Winkler A, Cohen S, Melnick A, MacKerell A Jr, Cierpicki T, Xue F J Med Chem. 2018 Sep 13;61(17):7573-7588. doi: 10.1021/acs.jmedchem.8b00040. Epub, 2018 Jul 17. PMID:29969259^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.