Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time
Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time
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DOI：
10.1042/bj20090121
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发表时间：
2009-06-01
影响因子：
4.1
通讯作者：
Yang, Jingsong
中科院分区：
文献类型：
--
作者：
Anderson, Kelly;Lai, Zhihong;Yang, Jingsong
Aurora激酶AurA， B和C是丝氨酸/苏氨酸蛋白激酶，在有丝分裂和细胞分裂中起重要作用。其中，Aura在有丝分裂过程中维持正确的染色体排列、分离和分离，并调节细胞质分裂过程中涉及的一些关键过程。AurB过表达已经在多种癌细胞系中被观察到，并且在小鼠异种移植模型中，抑制Aura基因被证明可以诱导肿瘤消退。在本研究中，我们报道了一种有效的选择性AurB/AurC抑制剂的酶学表征。GSK1070916是一种可逆的atp竞争性AurB-INCENP（内着丝粒蛋白）酶抑制剂。在爪蟾激酶样蛋白2靶蛋白AurA-TPX2 （K-i=490 +/- 60nM）上选择性抑制AurB-INCENP （K-i*=0.38 +/- 0.29nM）和AurC-INCENP （K-i*=1.5 +/- 0.4n M）。AurB-INCENP和AurC-INCENP的抑制是时间依赖性的。酶抑制剂解离半衰期分别为> 480 min和270 +/- 28 min。与Aura和AurC酶极慢的解离速率将GSK 1070916与临床中的另外两种Aurora抑制剂AZD1152和VX-680（也称为MK-0457）区分开来。
The Aurora kinases AurA, B and C are serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. Among them, Aura is required for maintaining proper chromosome alignment, separation and segregation during mitosis, and regulating a number of critical processes involved in cytokinesis. AurB overexpression has been observed in a variety of cancer cell lines, and inhibition of Aura leas been shown to induce tumour regression in mouse xenograft models. In the present study we report the enzymatic characterization of a potent and selective AurB/AurC inhibitor. GSK1070916 is a reversible and ATP-competitive inhibitor of the AurB-INCENP (inner centromere protein) enzyme. It selectively Inhibits AurB-INCENP (K-i*=0.38 +/- 0.29nM) and AurC-INCENP (K-i*=1.5 +/- 0.4n M) over AurA-TPX2 (target protein for Xenopus kinesin-like protein 2) (K-i=490 +/- 60nM). Inhibition of AurB-INCENP and AurC-INCENP is time-dependent. with an enzyme-inhibitor dissociation half-life of > 480 min and 270 +/- 28 min respectively. The extremely slow rate of dissociation from the Aura and AurC enzymes distinguishes GSK 1070916 from two other Aurora inhibitors in the clinic, AZD1152 and VX-680 (also known as MK-0457).