环戊并[ ]吲哚衍生物对原代细胞中的极光激酶B具有抑制作用。
Cyclopenta[]indole Derivative Inhibits Aurora B in Primary Cells.
作者信息
Ekebergh Andreas, Mårtensson Jerker, Ekebergh Christine Lingblom
机构信息
Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg 412 96, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 46, Sweden.
出版信息
ACS Omega. 2020 Dec 16;5(51):33455-33460. doi: 10.1021/acsomega.0c05491. eCollection 2020 Dec 29.
The Aurora family of kinases is closely involved in regulating cell division. Inhibition of Aurora A and B with small molecules is currently being investigated in clinical trials for the treatment of different cancers. It has also been evaluated as a treatment option against different autoimmune diseases in preclinical studies. Here, we present a cyclopenta[]indole derivative capable of inhibiting Aurora B selectively in kinase assays. To evaluate the Aurora B inhibition capacity of the compound, we used a kinase IC assay as well as a suppression assay of proliferating primary cells. In addition, we examined if the cells had gained a phenotype characteristic for Aurora B inhibition after treatment with the compound. We found that the compound selectively inhibited Aurora B (IC = 1.4 μM) over Aurora A (IC > 30 μM). Moreover, the compound inhibited proliferating PBMCs with an IC = 4.2 μM, and the cells displayed reduced phosphorylation of histone H3 as well as tetraploidy, consistent with Aurora B inhibition.
极光激酶家族密切参与细胞分裂的调控。目前，在针对不同癌症治疗的临床试验中，正在研究用小分子抑制极光激酶A和B。在临床前研究中，它也被评估为针对不同自身免疫性疾病的一种治疗选择。在此，我们展示了一种在激酶测定中能够选择性抑制极光激酶B的环戊并[ ]吲哚衍生物。为了评估该化合物对极光激酶B的抑制能力，我们使用了激酶IC测定法以及对增殖原代细胞的抑制测定法。此外，我们检查了在用该化合物处理后，细胞是否获得了极光激酶B抑制的表型特征。我们发现，该化合物对极光激酶B的选择性抑制作用（IC = 1.4 μM）优于极光激酶A（IC > 30 μM）。此外，该化合物以IC = 4.2 μM抑制增殖的外周血单核细胞，并且细胞显示出组蛋白H3磷酸化减少以及四倍体化，这与极光激酶B抑制一致。
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