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A Novel Ageladine A Derivative Acts as a STAT3 Inhibitor and Exhibits Potential Antitumor Effects

Na He1,2, Li Li1,3, Rui Li1,2

  • 1Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.

International Journal of Molecular Sciences
|May 27, 2023
PubMed

Insights

Compound 25, an ageladine A derivative, effectively inhibits Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling. This novel compound suppressed tumor growth in vivo and in vitro, showing potential as an antitumor agent.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is crucial for cell functions but its aberrant activation drives cancer progression.
  • Targeting the JAK/STAT3 pathway presents a promising strategy for developing novel antitumor therapies.

Purpose of the Study:

  • To synthesize and evaluate ageladine A derivatives as potential inhibitors of the JAK/STAT3 pathway.
  • To investigate the antitumor efficacy of the most potent compound, designated as compound 25.

Main Methods:

  • Synthesis of ageladine A derivatives and assessment of their inhibitory effects on STAT3 activity using a luciferase reporter assay.
  • Molecular docking studies to predict the binding interaction of compound 25 with the STAT3 SH2 domain.
  • Western blot analysis to evaluate the effect of compound 25 on STAT3 phosphorylation and downstream gene expression.
  • In vitro cell proliferation and migration assays using A549 and DU145 cancer cell lines.
  • In vivo studies using A549 xenograft models to assess the antitumor efficacy and safety of compound 25.

Main Results:

  • Compound 25 demonstrated the most significant inhibition of STAT3 luciferase activity among the synthesized derivatives.
  • Molecular docking indicated that compound 25 binds to the STAT3 SH2 domain.
  • Compound 25 selectively inhibited STAT3 phosphorylation at Tyr705, reducing downstream gene expression without affecting STAT1 or STAT5 phosphorylation.
  • Compound 25 suppressed the proliferation and migration of A549 and DU145 cells in vitro.
  • In vivo, compound 25 (10 mg/kg) effectively inhibited A549 xenograft tumor growth without significant adverse effects on body weight.

Conclusions:

  • Compound 25 is a potent inhibitor of JAK/STAT3 signaling, acting by blocking STAT3 phosphorylation.
  • Compound 25 exhibits significant antitumor activity in both in vitro and in vivo models.
  • These findings highlight compound 25 as a promising candidate for further development as an antitumor agent targeting the JAK/STAT3 pathway.
Keywords:
JAK/STAT3 signaling pathwaySTAT3 inhibitorsageladine A derivativesantitumor activitiesantitumor mechanismsdibromo pyrrole-imidazole

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