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Design,Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response |
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| Authors: | Dr Peng Liu Dr Xiangling Chen Dr Jianming Zhu Dr Bo Li Dr Zhaoqiang Chen Dr Guimin Wang Dr Haiguo Sun Dr Zhijian Xu Dr Zhixin Zhao Dr Chen Zhou Dr Chengying Xie Prof Liguang Lou Prof Weiliang Zhu |
| Institution: | 1. 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 These authors made equal contributions to this work.;2. 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 These authors made equal contributions to this work.;3. 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;4. 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;5. Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203 China |
| 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. |
| Keywords: | autophagy Hsp72 Hsp90 inhibitor triazines antitumor activity |