Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin.
Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin.
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DOI：
10.1038/onc.2011.335
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发表时间：
2012-03-15
期刊：
影响因子：
8
通讯作者：
Esteller, M.
中科院分区：
文献类型：
--
作者：
Huertas, D.;Soler, M.;Moreto, J.;Villanueva, A.;Martinez, A.;Vidal, A.;Charlton, M.;Moffat, D.;Patel, S.;McDermott, J.;Owen, J.;Brotherton, D.;Krige, D.;Cuthill, S.;Esteller, M.
组蛋白去乙酰酶抑制剂被批准用于治疗淋巴瘤亚型，使组蛋白修饰成为开发新型抗癌药物的潜在靶点。组蛋白也经历了磷酸化事件，而Haspin是一种蛋白激酶，其唯一已知的靶点是组蛋白H3在Th3残基(H3T3ph)的磷酸化，这是有丝分裂进程所必需的。有丝分裂酶可以被小剂量药物阻断，目前正在对这些药物进行几项临床试验。就像极光激酶抑制剂一样，Haspin可能是这些化合物药理开发的最佳候选者。对Haspin抑制剂的高通量筛选确定CHR-6494化合物是一种有前途的此类药物。我们证明了CHR-6494以剂量依赖的方式降低H3T3ph水平，并导致以中期错位、纺锤体异常和中心体放大为特征的有丝分裂灾难。从细胞的角度来看，已确定的小分子Haspin抑制剂可导致G2/M期细胞周期停滞，进而导致细胞凋亡。重要的是，体外试验也证明了它的抗血管生成功能；在体内，它在裸鼠移植瘤中显示出抗肿瘤的潜力，没有观察到任何毒性。因此，CHR-6494是一种一流的Haspin抑制剂，具有广泛的抗癌作用，值得作为有丝分裂酶抑制剂家族的新成员进行进一步的临床前研究。
The approval of histone deacetylase inhibitors for treatment of lymphoma subtypes has positioned histone modifications as potential targets for the development of new classes of anticancer drugs. Histones also undergo phosphorylation events, and Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph), which is necessary for mitosis progression. Mitotic kinases can be blocked by small drugs and several clinical trials are underway with these agents. As occurs with Aurora kinase inhibitors, Haspin might be an optimal candidate for the pharmacological development of these compounds. A high-throughput screening for Haspin inhibitors identified the CHR-6494 compound as being one promising such agent. We demonstrate that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly, ex vivo assays also demonstrate its anti-angiogenetic features; in vivo, it shows antitumor potential in xenografted nude mice without any observed toxicity. Thus, CHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects that merits further preclinical research as a new member of the family of mitotic kinase inhibitors.
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影响因子：
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