2. Academic Validation
  3. Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy

Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy

  • Eur J Med Chem. 2016 Feb 15:109:350-9. doi: 10.1016/j.ejmech.2016.01.013.
Jiachen Wen 1,  Yu Bao 2,  Qun Niu 1,  Jinyu Yang 1,  Yinbo Fan 1,  Jinhua Li 1,  Yongkui Jing 3,  Linxiang Zhao 4,  Dan Liu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: yongkui.jing@mssm.edu.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
  • 5 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
PMID: 26814680 DOI: 10.1016/j.ejmech.2016.01.013
Abstract

In this study, a collection of N-(6-mercaptohexyl)-3-substituted-1H-pyrazole-5-carboxamide HDAC inhibitors was developed. Among them, 15k was identified as the most potent inhibitor against total HDACs with IC50 of 0.008 μM. Further isoenzyme assays revealed that 15k and its analogs have a preference for HDAC1-3 (class I) and HDAC6 (class IIb) isoforms. The enzyme-based potencies of 15k were 2- to 11-fold higher than those of Vorinostat. The disulfide prodrug 18 was found to be potent cytotoxic agent against a panel of seven tumor cells, causing hyper-acetylation of histone and non-histone proteins in cellular level. In addition, 18 demonstrated a notable in vivo anti-tumor activity in HCT-116 xenografted model. This study provides further possibility of developing novel thiol-based HDAC inhibitors for the treatment of Cancer.

Keywords

Anti-tumor; Disulfide; Histone deacetylase inhibitor; Prodrug; Structure-activity relationship; Thiol.

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