Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth

Xia Li, Hongguang Ma, Lin Li, Yifan Chen, Xiao Sun, Zizheng Dong, Jing Yuan Liu, Weiming Zhu, Jian-Ting Zhang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and plays important roles in multiple aspects of cancer aggressiveness. Thus, targeting STAT3 promises to be an attractive strategy for the treatment of advanced metastatic tumors. Bisindolylmaleimide alkaloid (BMA) has been shown to have anti-cancer activities and was thought to suppress tumor cell growth by inhibiting protein kinase C. In this study, we show that a newly synthesized BMA analog, BMA097, is effective in suppressing tumor cell and xenograft growth and in inducing spontaneous apoptosis. We also provide evidence that BMA097 binds directly to the SH2 domain of STAT3 and inhibits STAT3 phosphorylation and activation, leading to reduced expression of STAT3 downstream target genes. Structure activity relationship analysis revealed that the hydroxymethyl group in the 2,5-dihydropyrrole-2,5-dione prohibits STAT3 inhibitory activity of BMA analogs. Altogether, we conclude that the synthetic BMA analogs may be developed as anti-cancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway.

Original languageEnglish (US)
Pages (from-to)2469-2480
Number of pages12
JournalOncogene
Volume37
Issue number18
DOIs
StatePublished - May 1 2018

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STAT3 Transcription Factor
src Homology Domains
Alkaloids
Heterografts
Transcriptional Activation
Breast Neoplasms
Growth
Neoplasms
bisindolylmaleimide
Drug Delivery Systems
Structure-Activity Relationship
Protein Kinase C
Phosphorylation
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. / Li, Xia; Ma, Hongguang; Li, Lin; Chen, Yifan; Sun, Xiao; Dong, Zizheng; Liu, Jing Yuan; Zhu, Weiming; Zhang, Jian-Ting.

In: Oncogene, Vol. 37, No. 18, 01.05.2018, p. 2469-2480.

Research output: Contribution to journalArticle

Li, Xia ; Ma, Hongguang ; Li, Lin ; Chen, Yifan ; Sun, Xiao ; Dong, Zizheng ; Liu, Jing Yuan ; Zhu, Weiming ; Zhang, Jian-Ting. / Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. In: Oncogene. 2018 ; Vol. 37, No. 18. pp. 2469-2480.
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AU - Sun, Xiao

AU - Dong, Zizheng

AU - Liu, Jing Yuan

AU - Zhu, Weiming

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