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


ABSTRACT: 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 invivo 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.

SUBMITTER: Liu P 

PROVIDER: S-EPMC6437812 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Liu Peng P   Chen Xiangling X   Zhu Jianming J   Li Bo B   Chen Zhaoqiang Z   Wang Guimin G   Sun Haiguo H   Xu Zhijian Z   Zhao Zhixin Z   Zhou Chen C   Xie Chengying C   Lou Liguang L   Zhu Weiliang W  

ChemistryOpen 20190328 3


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 t  ...[more]

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