Design, Synthesis, And Evaluation Of Cyanopyridines As Anti-Colorectal Cancer Agents Via Inhibiting STAT3 Pathway

Abstract

Background

Colorectal cancer is one of the common malignant tumors. Cyanopyridine and aminocyanopyridine having a carbon-nitrogen bond have been shown to have significant anticancer effects. STAT3 is a promising therapeutic target in multiple cancers. However, there are currently no effective STAT3 inhibitors in clinical practice for the treatment of colorectal cancer.

Materials and methods

We screened 27 cyanopyridines for their anticancer activity by cell viability. The HCT-116, RKO, and DLD-1 cell lines were used to evaluate the anti-colorectal cancer effect of 3n. Scratch experiments and colony formation assays were used for the assessment of cell migration and proliferation capacity. Phosphorylated STAT3, STAT3, MCL-1, and Survivin levels were assessed by Western blot analysis.

Results

In this study, we synthesized 27 cyanopyridines and screened their anticancer activities in three human tumor cells, HCT-116, Hela229, and A375. We found that 2-amino-3-cyanopyridine 3n has better anticancer activity with IC50 values in the low micromolar range. Furthermore, 3n significantly inhibited the migration and colony formation of colorectal cancer cells. Mechanistically, 3n inhibited the expression of STAT3 phosphorylation in a dose- and time-dependent manner.

Conclusion

3n is worth of further investigations toward the discovery of STAT3 inhibitor as a drug candidate for cancer therapy.

Keywords:

• design
• cyanopyridine
• colorectal cancer
• STAT3
• inhibitor

Acknowledgments

This work was financially supported by the Zhejiang Provincial Natural Science Fund (LY18H160047), National Natural Science Funding of China (21762006), Wenzhou Science and Technology Project (Y20190179), and Major Science and Technology Projects of Guangxi Zhuang Autonomous Region (No. AA17204090).

Disclosure

The authors report no conflicts of interest in this work.