State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
PLoS One. 2013;8(4):e59315. doi: 10.1371/journal.pone.0059315. Epub 2013 Apr 2.
Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization.
热休克蛋白 90（Hsp90）是一种有吸引力的抗癌靶点，其抑制剂在临床试验中显示出了有前景的活性。在这项工作中，我们首先通过生成 3D-QSAR 药效团模型来探索 Hsp90 抑制剂所需的显著药效团特征。然后，我们使用该模型对 SPECS 数据库进行虚拟筛选，鉴定出 17 个命中化合物。化合物 S1 和 S13 对 Hsp90 的抑制活性最强，IC50 值分别为 1.61±0.28 μM 和 2.83±0.67 μM。对这两种化合物与 Hsp90 的结合模式分析表明，它们具有合理的相互作用模式。进一步的评估表明，这些化合物对 HSP90 高表达的一系列癌细胞系表现出良好的抗增殖作用。同时，S13 在不同细胞系中以剂量依赖性方式诱导细胞凋亡。基于结合亲和力、理化性质和毒性的考虑，设计了 S13 的 24 个衍生物，得到了更有前途的化合物 S40，值得进一步优化。
