当前位置: X-MOL 学术J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-03 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00040
Huimin Cheng 1 , Brian M Linhares 2 , Wenbo Yu 1, 3 , Mariano G Cardenas 4 , Yong Ai 1 , Wenjuan Jiang 1, 3 , Alyssa Winkler 2 , Sandra Cohen 4 , Ari Melnick 4 , Alexander MacKerell 1, 3 , Tomasz Cierpicki 2 , Fengtian Xue 1, 3
Affiliation  

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.
更新日期:2018-07-03
down
wechat
bug