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

PMID: 30976475 (view PubMed database entry)
DOI: 10.1002/open.201900055 (read at publisher's website )
PMCID: PMC6437812 (free full text version available)

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Peng Liu, Xiangling Chen, Jianming Zhu, Bo Li, Zhaoqiang Chen, Guimin Wang, Haiguo Sun, Zhijian Xu, Zhixin Zhao, Chen Zhou, Chengying Xie, Liguang Lou, Weiliang Zhu,

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 (<b>A1</b>-<b>26</b>, <b>B1</b>-<b>13</b>, <b>C1</b>-<b>23</b>) as Hsp90 inhibitors. Compound <b>A14</b> 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, <b>A14</b> exhibited the most potent anti-proliferation ability by inducing autophagy, with the IC<sub>50</sub> values of 0.1 μM and 0.4 μM in A549 and SK-BR-3 cell lines, respectively. The <i>in</i>  <i>vivo</i> study demonstrated that <b>A14</b> could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti-tumor activity in A549 lung cancer xenografts. Therefore, the compound <b>A14</b> with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.

ChemistryOpen (ChemistryOpen)
[2019, 8(3):344-353]

Cited: 2 times

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