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首页> 外文期刊>Molecular informatics >Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through ShapeBased Similarity Screening
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Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through ShapeBased Similarity Screening

机译：通过基于形状的相似性筛选作为竞争性Hsp90抑制剂的新型吡唑并嘧啶类似物的发现和生物评价

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摘要

Hsp90 as a promising therapeutic target for the treatment of cancer has received great attention. Many Hsp90 inhibitors such as BIIB021 and CUDC-305 have been in clinical. In this paper shape-based similarity screening through ROCS overlays on the basis of CUDC-305, BIIB021, PU-H71 and PU-3 were performed to discover HSP90 inhibitors. A set of 19 novel pyrazolopyrimidine analogues was identified and evaluated on enzyme level and cell-based level as Hsp90 inhibitors. The compound HDI4-04 with IC50 0.35 mu M in the Hsp90 ATP hydrolysis assay exhibited potent cytotoxicity against five human cancer cell lines. Western blot analysis and Hsp70 luciferase reporter assay further confirmed that HDI4-04 targeted the Hsp90 protein folding machinery. And according to the biological assay, the SAR was discussed and summarized, which will guide us for further optimization of these compounds.
机译：Hsp90作为一种有前途的癌症治疗靶标受到了广泛的关注。许多Hsp90抑制剂（例如BIIB021和CUDC-305）已投入临床。在本文中，在CUDC-305，BIIB021，PU-H71和PU-3的基础上，通过ROCS叠加进行基于形状的相似性筛选，以发现HSP90抑制剂。鉴定了一组19种新颖的吡唑并嘧啶类似物，并在酶水平和基于细胞的水平上作为Hsp90抑制剂进行了评估。在Hsp90 ATP水解试验中，IC50为0.35μM的化合物HDI4-04对五种人类癌细胞系表现出有效的细胞毒性。蛋白质印迹分析和Hsp70荧光素酶报告基因检测进一步证实HDI4-04靶向Hsp90蛋白折叠机制。并根据生物学分析方法对SAR进行了讨论和总结，这将指导我们进一步优化这些化合物。

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