发现并研究新型二苯并噻唑衍生物作为 BTK 抑制剂的结构-活性关系，该抑制剂对 B 细胞淋巴瘤细胞系具有很强的活性。
Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines.
机构信息
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, PR China.
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, PR China.
出版信息
Eur J Med Chem. 2019 Sep 15;178:767-781. doi: 10.1016/j.ejmech.2019.06.035. Epub 2019 Jun 15.
By the analysis of different binding modes with Bruton's tyrosine kinase (BTK), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC = 1.36-8.60 μM) and Raji cell (IC = 1.20-14.04 μM) as compared with ibrutinib (IC = 14.69 and 15.99 μM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant BTK with IC value of 0.061 μM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited BTK Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of BTK inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.
通过对布鲁顿酪氨酸激酶（BTK）不同结合模式的分析，我们合理设计、合成并表征了一系列新型二苯并噻唑衍生物。在生化和细胞测定中的生物学评估表明，化合物 5m、5o、6b、6c、6g、6i、7h、7i、7k、7m、7n、7o 和 7s 对 Ramos 细胞（IC=1.36-8.60 μM）和 Raji 细胞（IC=1.20-14.04 μM）的抑制活性均优于伊布替尼（IC=14.69 和 15.99 μM）。特别是，化合物 7m 和 7n 对 Ramos 细胞活力的抑制活性比伊布替尼提高了 10 倍。化合物 6b 对 Raji 细胞活力的抑制活性比伊布替尼提高了 13 倍。此外，活性化合物 7o 对 C481S 突变 BTK 的抑制活性较强，IC 值为 0.061 μM。Ramos 和 Raji 细胞的凋亡分析表明，7o 比 CGI-1746 和伊布替尼更有效。7o 能有效抑制 Raji 细胞中 BTK 的 Y223 磷酸化，并使 Raji 和 Ramos 细胞的细胞周期停滞在 G0/G1 期。本研究扩展了 BTK 抑制剂的结构多样性，发现化合物 7o 是一种具有很大潜力的活性先导抑制剂，值得进一步研究。
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