School of Life Science and Medicine, Dalian University of Technology, Dagong Road No. 2, Panjin 124221, China.
Molecules. 2019 Jun 3;24(11):2105. doi: 10.3390/molecules24112105.
Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound showed the highest binding affinity to Hsp90α (IC = 12 nM) in fluorescence polarization (FP) competition assay and the strongest anti-proliferative activity against human breast adenocarcinoma cell line (MCF-7) and human lung epithelial cell line (A549) with IC values of 21.58 μM and 31.22 μM, respectively. Western blotting assays revealed that these novel Hsp90 inhibitors significantly down-regulated the expression level of Her2, a client protein of Hsp90, resulting in the cytotoxicity of these novel Hsp90 inhibitors. The molecular docking study showed that these novel Hsp90 inhibitors bound to the adenosine triphosphate (ATP) binding site at the N-terminus of Hsp90. Furthermore, structure-activity relationship studies indicated that the -benzyl group is important for the anti-cancer activity of 1,3-dibenzyl-2-aryl imidazolidines.
热休克蛋白 90（Hsp90）参与癌症发生和发展的各种过程，因此代表了癌症治疗有前途的药物靶标。在这项工作中，采用了虚拟筛选策略，从而鉴定出一系列具有 1,3-二苄基-2-芳基咪唑烷骨架的化合物作为新型 Hsp90 抑制剂。化合物在荧光偏振（FP）竞争测定中对 Hsp90α 的结合亲和力最高（IC = 12 nM），对人乳腺癌腺癌细胞系（MCF-7）和人肺上皮细胞系（A549）的抗增殖活性最强，IC 值分别为 21.58 μM 和 31.22 μM。Western blot 分析表明，这些新型 Hsp90 抑制剂显著下调了 Hsp90 的客户蛋白 Her2 的表达水平，导致这些新型 Hsp90 抑制剂的细胞毒性。分子对接研究表明，这些新型 Hsp90 抑制剂与 Hsp90 氨基末端的三磷酸腺苷（ATP）结合位点结合。此外，构效关系研究表明，-苄基对于 1,3-二苄基-2-芳基咪唑烷的抗癌活性很重要。
