Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases
Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases
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DOI：
10.1007/s10456-011-9212-6
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发表时间：
2011-09-01
期刊：
影响因子：
9.8
通讯作者：
Zahler, Stefan
中科院分区：
文献类型：
--
作者：
Liebl, Johanna;Krystof, Vladimir;Zahler, Stefan
细胞周期蛋白依赖性激酶（Cdks）的小分子抑制剂由于其抗增殖特性而目前被开发为抗癌治疗剂。嘌呤Cdk特异性抑制剂（R）-roscovitine（seliciclib，CYC 202）代表了这些化合物中最有前途的一种。它目前正在关于癌症治疗的临床试验中进行评估。最近，我们已经表明，roscovitine发挥有效的抗血管生成作用，并阐明Cdk 5作为一个新的球员在血管生成。这些发现引入了Cdk 5作为抗血管生成治疗的新靶点，并引入了Cdk 5抑制剂作为一种有吸引力的治疗方法。在这里，我们提出了15个衍生物的roscovitine在体外和体内的抗血管生成的档案，并提供roscovitine类似物的结构活性关系。（S）-异构体LGR 561和相应的（R）-和（S）-异构体LGR 848和LGR 849在体外强烈抑制增殖和细胞周期进展，诱导细胞死亡，并减少内皮细胞的迁移。与roscovitine相比，这些化合物显示出增加的抑制Cdk 2、Cdk 5、Cdk 7和Cdk 9的效力。通过分析LGR 561、LGR 848和LGR 849对内皮细胞管形成、小鼠主动脉环发芽、鸡胚绒毛尿囊膜中的血管生成和小鼠角膜中的新血管形成的作用，我们阐明了两种（S）-异构体LGR 561和LGR 849是高度有效的血管生成抑制剂。这项研究提供了关于如何修改roscovitine开发具有增加的抗血管生成活性的Cdk抑制剂的第一信息，并建议应用现有的和开发新的Cdk抑制剂来抑制癌细胞增殖和血管生成。
Small molecular inhibitors of Cyclin dependent kinases (Cdks) are currently being developed as anticancer therapeutics due to their antiproliferative properties. The purine Cdk specific inhibitor (R)-roscovitine (seliciclib, CYC202) represents one of the most promising of these compounds. It is currently evaluated in clinical trials concerning cancer therapy. Recently, we have shown that roscovitine exerts potent antiangiogenic effects and elucidated Cdk5 as a new player in angiogenesis. These findings introduce Cdk5 as novel target for antiangiogenic therapy, and Cdk5 inhibitors as an attractive therapeutic approach. Here, we present the antiangiogenic profile of 15 derivatives of roscovitine in vitro and in vivo and provide structure activity relationships of the roscovitine analogs. The (S)-isomer LGR561 and the respective (R)- and (S)-isomers LGR848 and LGR849 strongly inhibited proliferation and cell cycle progression, induced cell death, and reduced migration of endothelial cells in vitro. In comparison to roscovitine, these compounds showed an increased potency to inhibit Cdk2, Cdk5, Cdk7, and Cdk9. By analyzing the effects of LGR561, LGR848, and LGR849 on endothelial cell tube formation, mouse aortic ring sprouting, angiogenesis in the chick chorioallantoic membrane, and neovessel formation in the mouse cornea, we elucidate the two (S)-isomers LGR561 and LGR849 as highly potent inhibitors of angiogenesis. This study provides first information on how to modify roscovitine to develop Cdk inhibitors with increased antiangiogenic activity and suggests the application of existing and the development of new Cdk inhibitors to inhibit both, cancer cell proliferation and angiogenesis.