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ChemistryOpen Volume 8 ,Issue 3 ,2019-03-28
Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N‐terminal Inhibitors Without Induction of Heat Shock Response
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Peng Liu 1 , 2 Xiangling Chen 3 , 2 Jianming Zhu 1 Bo Li 1 , 2 Zhaoqiang Chen 1 , 2 Guimin Wang 1 , 2 Haiguo Sun 1 , 2 Zhijian Xu 1 , 2 Zhixin Zhao 3 Chen Zhou 3 Chengying Xie 3 , 2 Liguang Lou 3 , 2 Weiliang Zhu 1 , 2 , 4
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DOI:10.1002/open.201900055
Received 2019-02-03,
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摘要

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 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.

关键词

antitumor activity;triazines;Hsp90 inhibitor;Hsp72;autophagy

授权许可

© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

图表

Examples of Hsp90 NTD inhibitors. (A) GM and its derivatives. (B) Radicicol and its derivatives. (C) Purine analogues.

Synthesis of target compounds A1‐12, B1‐13 and C1‐23. a) NaHCO3, 4‐bromoaniline, room temperature, 3 hrs; b) 3,5‐dimethyl‐1H‐pyrazole, DIPEA, 120 °C, 10 hrs; c) 85 % hydrazine hydrate, room temperature; d) R2H, DIPEA, EtOH, room temperature, overnight; e) Aldehyde, AcOH, MeOH, reflux, 5 min.

Synthesis of target compounds A15‐26. a) R3H, DIPEA, 120 °C, 10 hrs; b) 85 % hydrazine hydrate, room temperature; c) Indole‐3‐carboxaldehyde, AcOH, MeOH, reflux, 5 min; d) R2H, DIPEA, EtOH, room temperature, overnight.

Summary of the structure–activity relationships of Hsp90 inhibitors.

The effect of the new compounds on HER2/Hsp72 and their binding to Hsp90. SK‐BR‐3 cells were treated with the compounds (20 μM) for 12 h, then the cells were harvested and lysed for western blot assay.

The effect of compounds on autophagy. (A) The effect of compounds on autophagy was observed under the microscope. (B) A549 and SK‐BR‐3 cells were treated with A1 (10 μM), A13, A14, A15 (3 μM), GM (1 μM) for 20 h. Whole‐cell lysates were analyzed by Western blotting using the indicated antibodies. (C) A549 and SK‐BR‐3 cells were treated with increasing concentration of compounds for 120 h. n=3; Error bars±SD.

Identification and characterization of compound A14 as a potent Hsp90α inhibitor. (A) SPR analysis of A14 binding to full‐length Hsp90α. Sensorgrams obtained by injection of A14 in a concentration‐dependent manner on immobilized Hsp90α. (B) A14 competed with FITC‐GM using FP assay. SNX for SNX‐2112. n=3; Error bars±SD. (C) Western blot analysis of SK‐BR‐3 following 12 h exposure to increasing concentrations of A14.

In vivo study of A14. (A) pharmacodynamics study of A14. A549 tumor‐bearing mice were administered a single 70‐mg/kg dose of A14. Tumor extracts were analyzed in parallel by Western blotting. (B) The quantification analysis of protein expression. (C) A549 tumor‐bearing mice were administered A14 (i. p.) daily for 14 days. Tumor volumes were measured twice a week. (D) The body weight of mice was measured twice a week. (E) Mice were sacrificed 9 h after the last dose, and tumors were removed and analyzed by Western blotting. (F) The quantification analysis of protein expression.

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通讯作者

1. Bo Li.Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China;University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing, 100049, China.boli@simm.ac.cn
2. Chengying Xie.Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China;University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing, 100049, China.boli@simm.ac.cn
3. Liguang Lou.Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China;University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing, 100049, China.boli@simm.ac.cn
4. Weiliang Zhu.Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China;University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing, 100049, China;Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China.boli@simm.ac.cn

推荐引用方式

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. Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N‐terminal Inhibitors Without Induction of Heat Shock Response. ChemistryOpen ,Vol.8, Issue 3(2019)

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