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

• Published in: ACS pharmacology & translational science Vol. 7; no. 9; pp. 2755 - 2783
• Main Authors: Oleksak, Patrik, Rysanek, David, Vancurova, Marketa, Vasicova, Pavla, Urbancokova, Alexandra, Novak, Josef, Maurencova, Dominika, Kashmel, Pavel, Houserova, Jana, Mikyskova, Romana, Novotny, Ondrej, Reinis, Milan, Juda, Pavel, Hons, Miroslav, Kroupova, Jirina, Sedlak, David, Sulimenko, Tetyana, Draber, Pavel, Chlubnova, Marketa, Nepovimova, Eugenie, Kuca, Kamil, Lisa, Miroslav, Andrys, Rudolf, Kobrlova, Tereza, Soukup, Ondrej, Janousek, Jiri, Prchal, Lukas, Bartek, Jiri, Musilek, Kamil, Hodny, Zdenek
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.09.2024
• Subjects: Medicin och hälsovetenskap; senolytics; covalent modifiers; glioblastoma; cellular senescence; mitotic poisons; inflammation
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.4c00190

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.