Merck Serono Research, Merck KGaA, Frankfurter Straße 250, D-64293 Darmstadt, Germany.
Bioorg Med Chem Lett. 2012 Jul 1;22(13):4396-403. doi: 10.1016/j.bmcl.2012.04.121. Epub 2012 May 5.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.
热休克蛋白 90（Hsp90）分子伴侣抑制剂作为癌症治疗的潜在分子治疗药物具有广阔的前景。在这里，我们描述了使用基于片段的方法鉴定新型小分子 Hsp90 抑制剂。通过对接选择片段，在生化测定中进行测试，并对确证的命中片段进行结晶。从这些片段和其他化学型的 X 射线结构中获得的信息用于驱动片段进化过程。对这些高 μM 结合物进行优化，得到了 3-苯并吲哚衍生物，它们在不同的人癌细胞系中具有显著改善的亲和力和抗增殖作用。
