MS-RTC-MedChem DA35, Merck Serono, Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. doi: 10.1016/j.bmcl.2010.01.110. Epub 2010 Jan 25.
Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.
在这里，我们描述了六氢-2H-吡喃并[3,2-c]喹啉（HHQPs）的发现和优化，它们是有丝分裂驱动蛋白-5 的有效且选择性抑制剂，最初是在高通量筛选（HTS）过程中从我们的内部化合物库中筛选出来的。随后优化并在此处进行了表征的化合物能够强烈抑制驱动蛋白-5 的 ATP 酶活性，并且还表现出一致的细胞活性，因为可以观察到细胞在有丝分裂和凋亡诱导中被阻滞。X 射线晶体学数据表明，这些抑制剂结合在驱动蛋白-5 的一个变构口袋中，远离核苷酸和微管结合位点。所选的临床候选药物 EMD 534085 在使用 Colo 205 结肠癌细胞的人肿瘤异种移植模型中，以低于 30mg/kg 的剂量每周两次给药两次，显示出强烈的生长抑制作用，而没有表现出严重的毒性，如体重减轻所确定的那样。
