Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.
Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.
复制标题
鉴定具有极光B同工型特异性的Aurora激酶抑制剂。
DOI：
10.1158/0008-5472.can-12-2784
复制
发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Xie H;Lee MH;Zhu F;Reddy K;Peng C;Li Y;Lim DY;Kim DJ;Li X;Kang S;Li H;Ma W;Lubet RA;Ding J;Bode AM;Dong Z
极光激酶在有丝分裂期间染色体排列、分离和胞质分裂中起重要作用。在本研究中，我们使用配体对接的方法来探索潜在的极光B抑制剂的新型支架。针对Aurora B结构筛选了来自我们内部化合物库的一千种化合物，并选择一种化合物（E）-3-（（E）-4-（苯并[d][1，3]间二氧杂环戊烯-5-基）-2-氧代丁-3-烯-1-亚基）二氢吲哚-2-酮（本文命名为HOI-07）用于进一步研究。HOI-07以剂量依赖性方式有效抑制体外Aurora B激酶活性，而对包括Aurora A在内的另外49种激酶无明显抑制作用。该化合物抑制肺癌细胞中的极光B激酶活性，通过以剂量和时间依赖性方式抑制组蛋白H3对Ser 10的磷酸化来证明。这种抑制导致细胞凋亡诱导、G2/M期阻滞、细胞多倍体和癌细胞非贴壁依赖性生长的减弱。此外，敲低Aurora B的表达有效地降低了癌细胞对HOI-07的敏感性。体内异种移植小鼠研究的结果显示，HOI-07处理有效地抑制了A549异种移植物的生长，而不影响小鼠的体重。HOI-07治疗组中磷酸化组蛋白H3、磷酸化极光B和Ki-67的表达也受到抑制。综上所述，我们确定HOI-07为特异性Aurora B抑制剂，值得进一步研究。
Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand-docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose- and time-dependent manner. This inhibition resulted in apoptosis induction, G2/M arrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation.