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 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.

• Authors: 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
• Journal: ChemistryOpen (ChemistryOpen) Vol. 8 Issue 3 Pg. 344-353 (Mar 2019) ISSN: 2191-1363 [Print] Germany
• PMID: 30976475 (Publication Type: Journal Article)