Discovery of a Novel Hybrid of Vorinostat and Riluzole as a Potent Antitumor Agent.

Qifu Xu,Jie Zang,Yingjie Zhang,Chunxi Liu,C James Chou,Shuai Gao

doi:10.3389/fcell.2020.00454

Abstract

Vorinostat (suberoylanilide hydroxamic acid) was the first approved histone deacetylase (HDAC) inhibitor in a group of validated cancer therapeutic agents targeting epigenetics. Riluzole is a drug used to treat amyotrophic lateral sclerosis, the antitumor potency of which has been recently revealed. Herein, a novel hybrid of vorinostat and riluzole (compound 1) was rationally designed, synthesized, and evaluated. Compared with vorinostat, compound 1 exhibited superior total HDAC inhibitory activity and similar HDAC isoform selective profiles. The intracellular HDAC inhibition of compound 1 was confirmed by Western blot analysis. Moreover, compound 1 possessed more potent in vitro antiproliferative activity against all tested solid and hematological tumor cell lines than vorinostat. In vitro metabolic stability evaluation of compound 1 revealed better human plasma stability and comparable human liver microsomal stability than vorinostat. Additionally, compound 1 demonstrated more significant in vivo antitumor activity in a MDA-MB-231 xenograft model than vorinostat, which could be attributed to its superior in vitro antiproliferative activity and metabolic stability. Taken together, the results presented here support further research and development of compound 1 as a promising antitumor agent.

Highlights

The acetylation status of lysine residues of nuclear histones, regulated by histone deacetylases (HDACs) and histone acetyl transferases (HATs), is one of the epigenetic mechanisms regulating gene expression (Allis and Jenuwein, 2016)
The introduction of various biologically active fragments, including nitrogen mustard (Xie et al, 2017), proapoptotic stilbene (Giacomini et al, 2014), colchicine (Zhang et al, 2013), and platinum complex (Griffith et al, 2009), to the cap part of vorinostat successfully led to corresponding hybrid molecules with antitumor potency (Figure 1)
Compound 1 was docked into the active site of HDAC2 (PDB code 4LXZ) using Tripos SYBYL-X 2.0

Summary

Introduction

The acetylation status of lysine residues of nuclear histones, regulated by histone deacetylases (HDACs) and histone acetyl transferases (HATs), is one of the epigenetic mechanisms regulating gene expression (Allis and Jenuwein, 2016). HDAC overexpression causes a low histone acetylation level, which can downregulate the expression of many genes, including tumor suppressor genes, leading to cancer (Falkenberg and Johnstone, 2014). Vorinostat [suberoylanilide hydroxamic acid (SAHA); Figure 1] is the first approved HDAC inhibitor. Its structure summarizes well the common pharmacophore of most HDAC inhibitors, which contain a zinc binding group (ZBG) that chelates the catalytic zinc ion, a hydrophobic linker that occupies the tunnel of the active site, and a terminal cap that interacts with the amino acid residues around the entrance of the Hybrid of Vorinostat and Riluzole active site (Miller et al, 2003). Structural modification of the terminal cap of vorinostat is a feasible and efficient strategy to develop novel HDAC inhibitors. The introduction of various biologically active fragments, including nitrogen mustard (Xie et al, 2017), proapoptotic stilbene (Giacomini et al, 2014), colchicine (Zhang et al, 2013), and platinum complex (Griffith et al, 2009), to the cap part of vorinostat successfully led to corresponding hybrid molecules with antitumor potency (Figure 1)

Methods

Results

Conclusion