East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences , East China Normal University , 200241 Shanghai , China.
Shanghai University of Traditional Chinese Medicine , Shanghai 200030 , China.
J Med Chem. 2020 Jan 23;63(2):676-695. doi: 10.1021/acs.jmedchem.9b01618. Epub 2020 Jan 13.
The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of -phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound -(3-chloro-4-methoxyphenyl)--isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of could effectively inhibit germinal center formation. More importantly, not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.
转录抑制剂 B 细胞淋巴瘤 6（BCL6）在弥漫性大 B 细胞淋巴瘤（DLBCL）中经常失调，已成为治疗淋巴瘤的有吸引力的药物靶点。在本文中，通过优化基于结构活性关系的命中化合物（3-氯-4-甲氧基苯基）-异丁基-5-氟-2,4-嘧啶二胺，设计并合成了一系列 -苯基-4-嘧啶胺衍生物，作为有效的 BCL6 抑制剂。其中，化合物显示出最强的活性，能显著阻断 BCL6 与其核心抑制剂的相互作用，以剂量依赖性方式重新激活 BCL6 靶基因，与两种阳性对照相比具有更好的效果。进一步的研究表明，低剂量的 可有效抑制生发中心的形成。更重要的是， 不仅在体外表现出对 DLBCL 细胞增殖的强烈抑制作用，而且在体内也强烈抑制了 DLBCL 的生长。
