2. Academic Validation
  3. Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

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

  • J Enzyme Inhib Med Chem. 2022 Dec;37(1):236-251. doi: 10.1080/14756366.2021.2001805.
Shaohua Xu 1,  Ruolan Fan 1,  Lu Wang 2,  Weishen He 3,  Haixia Ge 4,  Hailan Chen 1,  Wen Xu 1,  Jian Zhang 5,  Wei Xu 1,  Yaqian Feng 6,  Zhimin Fan 2
Affiliations

Affiliations

  • 1 College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, P.R. China.
  • 2 National Center of Colorectal Disease, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, P.R. China.
  • 3 Biology Department, Boston College, Brighton, MA, USA.
  • 4 School of Life Sciences, Huzhou University, Huzhou, P.R. China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China.
  • 6 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, P.R. China.
PMID: 34894961 DOI: 10.1080/14756366.2021.2001805
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; STAT3 inhibitor; anti-tumour; colorectal cancer organoid; structural modification.

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