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

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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 (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.

更新日期：2018-07-03

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