Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

Abstract

Using STAT3 inhibitors as a potential strategy in cancer therapy have attracted much attention. Recently, celastrol has been reported that it could directly bind to and suppress the activity of STAT3 in the cardiac dysfunction model. To explore more effective STAT3 inhibiting anti-tumour drug candidates, we synthesised a series of celastrol derivatives and biologically evaluated them with several human cancer cell lines. The western blotting analysis showed that compound 4 m, the most active derivative, could suppress the STAT3’s phosphorylation as well as its downstream genes. SPR analysis, molecular docking and dynamics simulations’ results indicated that the 4m could bind with STAT3 protein more tightly than celastrol. Then we found that the 4m could block cell-cycle and induce apoptosis on HCT-116 cells. Furthermore, the anti-tumour effect of 4m was verified on colorectal cancer organoid. This is the first research that discovered effective STAT3 inhibitors as potent anti-tumour agents from celastrol derivatives.

Keywords:

• Celastrol
• structural modification
• anti-tumour
• STAT3 inhibitor
• colorectal cancer organoid

Acknowledgements

The authors thank Dr. Shuai Lu, the associate professor of China Pharmaceutical University, for carrying out the ADMET analysis.

Ethical approval

Ethical approval of organoid sample bank was given by the Ethics Board of Nanjing Hospital of Chinese Medicine with the following reference number: KY2019071.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

The work was supported by the Natural Science Foundation of Fujian Province [2020J05062], the Education and Research Projects for Young and Middle-aged Teachers of Fujian Educational Department [JAT190240], Nanjing Clinical Research Centre of Anorectal Diseases of Traditional Chinese Medicine [20190610] and the Scientific Research Foundation for the High-level Talents and Fujian University of Traditional Chinese Medicine [X2019003-Professional].