Department of Pharmaceutical Sciences , University of Maryland School of Pharmacy , 20 Penn Street , Baltimore , Maryland 21201 , United States.
Department of Pathology , University of Michigan , Ann Arbor , Michigan 48109 , United States.
J Med Chem. 2018 Sep 13;61(17):7573-7588. doi: 10.1021/acs.jmedchem.8b00040. Epub 2018 Jul 17.
Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6 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. 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. 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.
蛋白质-蛋白质相互作用（PPI）之间的转录抑制因子 B 细胞淋巴瘤 6（BCL6） BTB 结构域（BCL6）和其共抑制因子已成为癌症治疗的一个有前途的目标。然而，鉴定有效的、类似药物的 BCL6 抑制剂仍然具有挑战性。我们使用基于 NMR 的片段小分子文库筛选，鉴定出与 BCL6 结合的硫脲化合物（7CC5）。从这个命中化合物出发，应用计算机辅助药物设计（CADD）、药物化学、NMR 光谱学和 X 射线晶体学，得到了一种抑制剂 15f，其对 BCL6 的活性提高了 100 多倍。这种效力的提高是通过一种独特的结合模式实现的，该模式模拟了共抑制因子 SMRT 在芳香族和 HDCH 位点的结合模式。基于这些新抑制剂的结构-活性关系将对新型 BCL6 抑制剂的合理设计产生重大影响，有助于鉴定用于治疗 BCL6 依赖性肿瘤的治疗药物。
