Europe PMC b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities.">b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities.">
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Discovery of a 6-Aminobenzo[b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities.

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Affiliations

  • 1. Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic.
      Authors
    • Oleksak P 1
    • Chlubnova M 1
    • Nepovimova E 1
    • Kuca K 1
    • Lisa M 1
    • Andrys R 1
    • Musilek K 1
    (7 authors)
  • 2. Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
      Authors
    • Rysanek D 2
    • Vancurova M 2
    • Vasicova P 2
    • Urbancokova A 2
    • Novak J 2
    • Maurencova D 2
    • Kashmel P 2
    • Houserova J 2
    • Kroupova J 2
    • Bartek J 2
    • Hodny Z 2
    (11 authors)
  • 3. Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
      Authors
    • Mikyskova R 3
    • Novotny O 3
    • Reinis M 3
    (3 authors)
  • 4. BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec 252 50, Czech Republic.
      Authors
    • Juda P 4
    • Hons M 4
    (2 authors)
  • 5. CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic.
      Authors
    • Sedlak D 5
    (1 author)
    • Show all (7)

ORCIDs linked to this article

Show all (11)

ACS Pharmacology & Translational Science, 12 Aug 2024, 7(9):2755-2783
https://doi.org/10.1021/acsptsci.4c00190 PMID: 39296273 

Free full text available after 12 Aug 2025

Abstract 

6-Nitrobenzo[b]thiophene 1,1-dioxide (Stattic) is a potent signal transducer and activator of the transcription 3 (STAT3) inhibitor developed originally for anticancer therapy. However, Stattic harbors several STAT3 inhibition-independent biological effects. To improve the properties of Stattic, we prepared a series of analogues derived from 6-aminobenzo[b]thiophene 1,1-dioxide, a compound directly obtained from the reduction of Stattic, that includes a methoxybenzylamino derivative (K2071) with optimized physicochemical characteristics, including the ability to cross the blood-brain barrier. Besides inhibiting the interleukin-6-stimulated activity of STAT3 mediated by tyrosine 705 phosphorylation, K2071 also showed cytotoxicity against a set of human glioblastoma-derived cell lines. In contrast to the core compound, a part of K2071 cytotoxicity reflected a STAT3 inhibition-independent block of mitotic progression in the prophase, affecting mitotic spindle formation, indicating that K2071 also acts as a mitotic poison. Compared to Stattic, K2071 was significantly less thiol-reactive. In addition, K2071 affected cell migration, suppressed cell proliferation in tumor spheroids, exerted cytotoxicity for glioblastoma temozolomide-induced senescent cells, and inhibited the secretion of the proinflammatory cytokine monocyte chemoattractant protein 1 (MCP-1) in senescent cells. Importantly, K2071 was well tolerated in mice, lacking manifestations of acute toxicity. The structure-activity relationship analysis of the K2071 molecule revealed the necessity of the para-substituted methoxyphenyl motif for antimitotic but not overall cytotoxic activity of its derivatives. Altogether, these results indicate that compound K2071 is a novel Stattic-derived STAT3 inhibitor and a mitotic poison with anticancer and senotherapeutic properties that is effective on glioblastoma cells and may be further developed as an agent for glioblastoma therapy.

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Read article at publisher's site: https://doi.org/10.1021/acsptsci.4c00190

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