Sanofi-Aventis Research and Development, 13 Quai Jules Guesde, BP 14, 94400 Vitry-sur-Seine, France.
J Med Chem. 2011 Oct 27;54(20):7206-19. doi: 10.1021/jm200784m. Epub 2011 Oct 5.
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
开发了一种新型热休克蛋白 90（Hsp90）抑制剂，方法是对包含约 21000 个化合物的重点库进行低通量筛选（LTS），这些化合物是通过虚拟筛选选择的。最初的[1-{3-H-咪唑并[4-5-c]吡啶-2-基}-3,4-二氢-2H-吡啶并[2,1-a]异吲哚-6-酮]（1）化合物显示出中等活性（对 Hsp82 的 IC50=7.6 μM，Hsp82 是 Hsp90 的酵母同源物）。高分辨率 X 射线结构表明，化合物 1 结合到一个“诱导”的疏水性口袋中，距离 ATP/间苯二酚结合位点 10-15 Å。基于结构的药物设计（SBDD）和化学合成的迭代循环导致设计和制备了具有改善亲和力的类似物。正如其他 Hsp90 抑制剂所报道的那样，这些优化的分子在 ATP 结合位点中产生了有成效的相互作用。这导致了化合物 8 的产生，它在生化和细胞测定中是一种非常有效的抑制剂（对 Hsp90 的 Kd=0.35 nM；对 SKBr3 乳腺癌细胞的 IC50=30 nM），并在体内白血病模型中也是如此。
