Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase
Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase
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DOI：
10.1021/jm901870q
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发表时间：
2010-05-27
影响因子：
7.3
通讯作者：
Dhanak, Dashyant
中科院分区：
文献类型：
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作者：
Adams, Nicholas D.;Adams, Jerry L.;Dhanak, Dashyant
极光激酶在有丝分裂的调节中发挥着关键作用，并且在人类肿瘤中经常过度表达或扩增。选择性抑制剂可能为极光激酶扩增的肿瘤治疗提供新疗法。在此，我们描述了我们在基于 7-氮杂吲哚的系列中的先导优化工作，最终鉴定出 GSK1070916 (17k)。该系列进展的关键是将含有碱性胺的 2-芳基引入氮杂吲哚上，从而显着提高细胞活性。化合物 17k 是 Aurora B 和 C 的有效选择性 ATP 竞争性抑制剂，K(i)* 值分别为 0.38 +/- 0.29 和 1.5 +/- 0.4 nM，选择性比 Aurora A 高 250 倍。生化表征表明，化合物 17k 与 Aurora B 的解离半衰期极慢（> 480 分钟），这使其与临床药物区别开来。化合物 1 和 2。用化合物 17k 体外处理 A549 人肺癌细胞可产生有效的抗增殖作用 (EC(50) = 7 nM）。在携带人类肿瘤异种移植物的小鼠中腹膜内施用 17k 可抑制人类结肠癌 (Colo205) 中丝氨酸 10 的组蛋白 H3 磷酸化和人类白血病 (HL-60) 中的肿瘤消退。化合物 17k 正在进入人体临床试验。
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is > 250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.