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

6-Nitrobenzo[<i>b</i>]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[<i>b</i>]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 <i>para</i>-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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Journal
ACS Pharmacology & Translational Science
Published
2024-08-12
DOI
https://doi.org/10.1021/acsptsci.4c00190
Citations
1
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
0.28

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article

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

Miroslav Lísa, Miroslav Hons, Romana Mikyšková, Pavel Dráber et al.
1 citations
ACS Pharmacology & Translational Science
Cytokine Signaling Pathways and Interactions
0.28
article

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

Miroslav Lísa, Miroslav Hons, Romana Mikyšková, Pavel Dráber, Ondřej Soukup, Eugenie Nepovimová, Zdeněk Hodný, Rudolf Andrýs, Milan Reiniš, Tetyana Sulimenko, Patrik Olekšák, Jiří Janoušek, Pavel Jůda, Lukáš Prchal, Tereza Kobrlová, Josef Novák, David Sedlák, David Rysanek, Kamil Musílek, Kamil Kuča, M Vancurová, Ondrej Novotny, Jiřina Kroupová, Pavla Vašicová, Jana Houserová, Jiří Bártek, Alexandra Urbancokova, Marketa Chlubnova, Dominika Maurencova, Pavel Kashmel
article en
1 citations

Abstract

6-Nitrobenzo[<i>b</i>]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[<i>b</i>]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 <i>para</i>-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.

ACS Pharmacology & Translational ScienceVol. 7(9)
Charles University (CZ), Science for Life Laboratory (SE), Karolinska Institutet (SE), University Hospital Hradec Králové (CZ), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Danish Cancer Society (DK), University of Hradec Králové (CZ)
Univerzita Karlova v Praze, Univerzita Hradec Králové, Fakultní nemocnice Hradec Králové, European Commission, Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Karolinska Institutet, Akademie Věd České Republiky, Science for Life Laboratory, Agentura Pro Zdravotnický Výzkum České Republiky, Ústav Molekulární Genetiky, Akademie Věd České Republiky, HORIZON EUROPE Marie Sklodowska-Curie Actions
Openalex Percentile: Top 37%
Cytokine Signaling Pathways and Interactions
0.28
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