Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N‐terminal Inhibitors Without Induction of Heat Shock Response

Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (A1‐26, B1‐13, C1‐23) as Hsp90 inhib...

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Published in:ChemistryOpen (Weinheim) 2019-03, Vol.8 (3), p.344-353
Main Authors: Liu, Peng, Chen, Xiangling, Zhu, Jianming, Li, Bo, Chen, Zhaoqiang, Wang, Guimin, Sun, Haiguo, Xu, Zhijian, Zhao, Zhixin, Zhou, Chen, Xie, Chengying, Lou, Liguang, Zhu, Weiliang
Format: Article
Language:English
Subjects:
Anticancer properties
antitumor activity
autophagy
Binding sites
Breast cancer
Cells
Chlorine
Cytotoxicity
Heat shock proteins
Hsp72
Hsp90 inhibitor
Hydrocarbons
In vivo methods and tests
Inhibitors
Kinases
Lung cancer
Pharmacology
Proteins
triazines
Xenotransplantation
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Summary:Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (A1‐26, B1‐13, C1‐23) as Hsp90 inhibitors. Compound A14 directly bound to Hsp90 in a different manner from traditional Hsp90 inhibitors, and degraded client proteins, but did not induce the concomitant activation of Hsp72. Importantly, A14 exhibited the most potent anti‐proliferation ability by inducing autophagy, with the IC50 values of 0.1 μM and 0.4 μM in A549 and SK‐BR‐3 cell lines, respectively. The in vivo study demonstrated that A14 could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti‐tumor activity in A549 lung cancer xenografts. Therefore, the compound A14 with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response. No shock to the system! A series of novel X66 derivatives are designed and synthesized and their antiproliferative properties are discussed. Some compounds show better cytotoxicity profiles. In vivo study revealed that A14 could degrade Hsp90 client proteins HER2 and AKT in tumor tissues, induced autophagy, and exhibited anti‐tumor activity in A549 lung cancer xenografts.
ISSN:2191-1363
2191-1363
DOI:10.1002/open.201900055