发现新型伊布替尼类似物治疗恶性黑色素瘤。
Discovery of novel ibrutinib analogues to treat malignant melanoma.
机构信息
School of Pharmaceutical Sciences, Nation-Regional Engineering Lab for Synthetic Biology of Medicine, International Cancer Center, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, China; Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China.
School of Pharmaceutical Sciences, Nation-Regional Engineering Lab for Synthetic Biology of Medicine, International Cancer Center, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong, China.
出版信息
Bioorg Chem. 2021 Dec;117:105419. doi: 10.1016/j.bioorg.2021.105419. Epub 2021 Oct 12.
A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC value in B16 cells was almost 9-fold better than that of ibrutinib. Mechanism of action studies showed that YL7 inhibited proliferation and migration and induced G1 cell cycle arrest, apoptosis and autophagy in B16 cells. Further assessment of in vivo antitumor efficacies demonstrated that YL7 significantly inhibited the growth of B16 melanoma. These preliminary studies suggest that it is reasonable to modify the structure of ibrutinib for antimelanoma treatment.
合成了一系列新型伊布替尼类似物，并评估了它们对各种 B 淋巴瘤细胞系（DaudiB 和 Raji）和实体肿瘤细胞（B16、CT26、HepG2 和 4T1）的增殖抑制活性。最有效的化合物 YL7 在所有细胞系中均表现出强烈的增殖抑制活性，其在 B16 细胞中的 IC 值比伊布替尼低近 9 倍。作用机制研究表明，YL7 抑制增殖和迁移，并诱导 B16 细胞 G1 细胞周期停滞、凋亡和自噬。体内抗肿瘤疗效的进一步评估表明，YL7 能显著抑制 B16 黑色素瘤的生长。这些初步研究表明，对伊布替尼进行结构修饰用于抗黑色素瘤治疗是合理的。
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