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

Cheng, Huimin; Linhares, Brian M.; Yu, Wenbo; Cardenas, Mariano G.; Ai, Yong; Jiang, Wenjuan; Winkler, Alyssa; Cohen, Sandra; Melnick, Ari; MacKerell, Alexander; Cierpicki, Tomasz; Xue, Fengtian

doi:10.1021/acs.jmedchem.8b00040

Title: Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design

Journal Article · Tue Jul 03 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00040· OSTI ID:1569870

Cheng, Huimin ^[1]; Linhares, Brian M. ^[2]; Yu, Wenbo ^[1]; Cardenas, Mariano G. ^[3]; Ai, Yong ^[1]; Jiang, Wenjuan ^[1]; Winkler, Alyssa ^[2]; Cohen, Sandra ^[3]; Melnick, Ari ^[3];

^[1]; Cierpicki, Tomasz ^[2];

^[1]

Univ. of Maryland, Baltimore, MD (United States)
Univ. of Michigan, Ann Arbor, MI (United States)
Weill Cornell Medical College, New York, NY (United States)

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. Overall, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; American Association for Cancer Research

Grant/Contract Number:: 00167155

OSTI ID:: 1569870

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 17; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 28 works

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Title: Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design

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