Synthesis and Biological Evaluation of B‑Cell Lymphoma 6 Inhibitors of N‑Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth

• Published in: Journal of medicinal chemistry 2020-01, Vol.63 (2), p.676-695
• Main Authors: Guo, Weikai, Xing, Yajing, Zhang, Qiansen, Xie, Jiuqing, Huang, Dongxia, Gu, Haijun, He, Peng, Zhou, Miaoran, Xu, Shifen, Pang, Xiufeng, Liu, Mingyao, Yi, Zhengfang, Chen, Yihua
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01618

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 N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N 4-(3-chloro-4-methoxyphenyl)-N 2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure–activity relationship. Among them, compound 14j 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 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.