Peifer Christian, Stoiber Thomas, Unger Eberhard, Totzke Frank, Schächtele Christoph, Marmé Dieter, Brenk Ruth, Klebe Gerhard, Schollmeyer Dieter, Dannhardt Gerd
Department of Pharmacy, Johannes Gutenberg-University, Staudingerweg 5, D-55099 Mainz, Germany.
J Med Chem. 2006 Feb 23;49(4):1271-81. doi: 10.1021/jm0580297.
The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in a panel of 12 selected protein kinases and a high affinity of 10 to VEGF-R2 was found showing an IC50 of 2.5 nM. Structure-activity relationships (SAR) for this compound series with the isolated enzyme and equivalent antiangiogenic activity in the chick embryo assay are presented herein.
新的康普他汀A - 4类似物2被发现是一种微管蛋白聚合抑制剂，其IC50为7.6微摩尔，并且在体内鸡胚模型中可减少血管生成。有趣的是，在与该先导化合物密切相关的一系列2,3 - 二芳基马来酰亚胺中，未发现其他化合物在微管蛋白聚合试验中具有活性。然而，通过在体内鸡胚试验中进行筛选，化合物10被鉴定为一种有效的血管生成抑制剂，表明存在另一种靶点。实际上，分子模拟研究表明化合物10在模型激酶CDK2的ATP结合位点具有合理的结合模式。受这些结果的推动，对化合物10的类似物在一组12种选定的蛋白激酶中进行了抑制活性筛选，发现化合物10对血管内皮生长因子受体2（VEGF - R2）具有高亲和力，其IC50为2.5纳摩尔。本文介绍了该化合物系列与分离酶的构效关系（SAR）以及在鸡胚试验中的等效抗血管生成活性。
