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

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.07 Pathology
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: p. 7573-7588 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260200
• Chủ đề: 1. 60 applied life sciences; 2. Crystal structure; 3. Electron correlation; 4. Functional groups; 5. Indoles; 6. Inhibitors

Tóm tắt

 Protein?protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6<
 sup>
 BTB<
 /sup>
 ) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6<
 sup>
 BTB<
 /sup>
  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<
 sup>
 BTB<
 /sup>
 . 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<
 sup>
 BTB<
 /sup>
 . 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.