Cyclophilin J PPIase Inhibitors Derived from 2,3-Quinoxaline-6 Amine Exhibit Antitumor Activity.

Xuemei Zhao,Ming Xin,Chengcai Xia,Hao Wang,Xiaodan Wang,Yulong Liang,Long Yu

doi:10.3389/fphar.2018.00126

Xuemei Zhao, Ming Xin + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2018.00126

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Abstract

Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis–trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC. These findings suggest that CyPJ may be a potential therapeutic target for HCC, and discovery of relevant inhibitors may facilitate development of a novel CyPJ-based targeting therapy. However, apart from the common inhibitor CsA, CyPJ has yet to be investigated as a target for cancer therapy. Here, we report structure-based identification of novel small molecule non-peptidic CyPJ inhibitors and their potential as antitumor lead compounds. Based on computer-aided virtual screening, in silico, and subsequently surface plasmon resonance analysis, 19 potential inhibitors of CyPJ were identified and selected for further evaluation of PPIase CyPJ inhibition in vitro. Thirteen out of 19 compounds exhibited notable inhibition against PPIase activity. Among them, the compound ZX-J-19, with a quinoxaline nucleus, showed potential for tumor inhibition; thus, we selected it for further structure–activity optimization. A total of 22 chemical derivatives with 2,3-substituted quinoxaline-6-amine modifications were designed and successfully synthesized. At least 2 out of the 22 derivatives, such as ZX-J-19j and ZX-J-19l, demonstrated remarkable inhibition of tumor cell growth, comparable to CsA but much stronger than 5-fluorouracil. These results indicate that these two small molecules represent novel potential lead compounds for CyPJ-based antitumor drug development.

Highlights

Cyclophilins constitute a superfamily of peptidylprolyl isomerases (PPIase), which catalyze the cis–trans isomerization of peptide bonds on the N-terminal side of proline residue (Harikishore and Yoon, 2015; Dunyak and Gestwicki, 2016)
We identified its peptidylprolyl cis–trans isomerase (PPIase) activity, which could be inhibited by cyclosporine A (CsA) (Chen et al, 2015)
Crystal structures of Cyclophilin J (CyPJ) complexed with CsA were analyzed for potential inhibitory ligands (Huang et al, 2005; Chen et al, 2015)

Summary

Introduction

Cyclophilins constitute a superfamily of peptidylprolyl isomerases (PPIase), which catalyze the cis–trans isomerization of peptide bonds on the N-terminal side of proline residue (Harikishore and Yoon, 2015; Dunyak and Gestwicki, 2016). Cyclophilins have been shown to act as chaperones accelerating protein folding and maturation, as well as playing a critical role in signal transduction and the immune response (Gothel and Marahiel, 1999; Wang and Heitman, 2005; Lucke and Weiwad, 2011; Harikishore and Yoon, 2015). Cyclophilin J (CyPJ), known as peptidylprolyl isomerase like 3 (PPIL3), is a new member of the cyclophilin family, with human CyPJ being first reported in 2001 (Zhou et al, 2001). Its protein sequence exhibits 50% identity to human cyclophilin A and 72% identity to cyclophilin isoform 10 of Caenorhabditis elegans (Zhou et al, 2001)

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