0598575 - ÚMG 2025 RIV US eng J - Článek v odborném periodiku
Oleksak, P. - Ryšánek, David - Vančurová, Markéta - Vašicová, Pavla - Urbančoková, Alexandra - Novák, Josef - Maurencová, Dominika - Kashmel, Pavel - Houserová, Jana - Mikyšková, Romana - Novotný, Ondřej - Reiniš, Milan - Juda, P. - Hons, M. - Kroupová, Jiřina - Sedlák, David - Sulimenko, Tetyana - Dráber, Pavel - Chlubnová, M. - Nepovimová, E. - Kuča, K. - Lísa, M. - Andrýs, R. - Kobrlová, T. - Soukup, O. - Janoušek, J. - Prchal, L. - Bártek, Jiří - Musílek, K. - Hodný, Zdeněk
Discovery of a 6-Aminobenzobthiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities.
ACS Pharmacology & Translational Science. Roč. 7, č. 9 (2024), s. 2755-2783. E-ISSN 2575-9108
Grant CEP: GA ČR GA20-15728S; GA MZd NV18-05-00562; GA MŠMT LX22NPO5102; GA MŠMT(CZ) LM2023050; GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) LM2018130
Institucionální podpora: RVO:68378050
Klíčová slova: interleukin-6 promotes * cell-proliferation * stat3 * cancer * checkpoint * senescence * migration * brain * covalent modifiers * glioblastoma * mitotic poisons * cellular senescence * senolytics * inflammation
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.9, rok: 2023
Způsob publikování: Open access
Web výsledku:
https://pubs.acs.org/doi/10.1021/acsptsci.4c00190DOI: https://doi.org/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.
Trvalý link: https://hdl.handle.net/11104/0356348