Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape‐Based Similarity Screening
Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape‐Based Similarity Screening
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DOI：
10.1002/minf.201300150
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发表时间：
2014-04
影响因子：
3.6
通讯作者：
Xiaoli Xu;Haopeng Sun;Fang Liu;Jianmin Jia;Xiaoke Guo;Yang Pan;Hao-Ze Huang;Xiaojin Zhang
中科院分区：
文献类型：
--
作者：
Xiaoli Xu;Haopeng Sun;Fang Liu;Jianmin Jia;Xiaoke Guo;Yang Pan;Hao-Ze Huang;Xiaojin Zhang
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 µM 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.
