Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

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

P. Oleksak, D. Rysanek, M. Vancurova, P. Vasicova, A. Urbancokova, J. Novak, D. Maurencova, P. Kashmel, J. Houserova, R. Mikyskova, O. Novotny, M. Reinis, P. Juda, M. Hons, J. Kroupova, D. Sedlak, T. Sulimenko, P. Draber, M. Chlubnova, E....

. 2024 ; 7 (9) : 2755-2783. [pub] 20240812

Status neindexováno Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24017823

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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24017823
003      
CZ-PrNML
005      
20250506100632.0
007      
ta
008      
241008s2024 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acsptsci.4c00190 $2 doi
035    __
$a (PubMed)39296273
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Oleksak, Patrik $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic $1 https://orcid.org/0000000268507671
245    10
$a 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 / $c P. Oleksak, D. Rysanek, M. Vancurova, P. Vasicova, A. Urbancokova, J. Novak, D. Maurencova, P. Kashmel, J. Houserova, R. Mikyskova, O. Novotny, M. Reinis, P. Juda, M. Hons, J. Kroupova, D. Sedlak, T. Sulimenko, P. Draber, M. Chlubnova, E. Nepovimova, K. Kuca, M. Lisa, R. Andrys, T. Kobrlova, O. Soukup, J. Janousek, L. Prchal, J. Bartek, K. Musilek, Z. Hodny
520    9_
$a 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.
590    __
$a NEINDEXOVÁNO
655    _2
$a časopisecké články $7 D016428
700    1_
$a Rysanek, David $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic $1 https://orcid.org/0000000251310055
700    1_
$a Vancurova, Marketa $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Vasicova, Pavla $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Urbancokova, Alexandra $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Novak, Josef $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Maurencova, Dominika $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Kashmel, Pavel $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Houserova, Jana $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Mikyskova, Romana $u Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Novotny, Ondrej $u Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Reinis, Milan $u Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic $1 https://orcid.org/0000000170832898
700    1_
$a Juda, Pavel $u BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec 252 50, Czech Republic $1 https://orcid.org/0000000264213852
700    1_
$a Hons, Miroslav $u BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec 252 50, Czech Republic
700    1_
$a Kroupova, Jirina $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic $1 https://orcid.org/0000000279466975
700    1_
$a Sedlak, David $u CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic $1 https://orcid.org/000000030074335X $7 xx0119393
700    1_
$a Sulimenko, Tetyana $u Laboratory of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Draber, Pavel $u Laboratory of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
700    1_
$a Chlubnova, Marketa $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
700    1_
$a Nepovimova, Eugenie $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
700    1_
$a Kuca, Kamil $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic $1 https://orcid.org/0000000196641109 $7 xx0041831
700    1_
$a Lisa, Miroslav $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic $1 https://orcid.org/0000000192275375 $7 xx0090411
700    1_
$a Andrys, Rudolf $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
700    1_
$a Kobrlova, Tereza $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
700    1_
$a Soukup, Ondrej $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic $1 https://orcid.org/0000000163768701 $7 xx0253350
700    1_
$a Janousek, Jiri $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
700    1_
$a Prchal, Lukas $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic
700    1_
$a Bártek, Jiří, $d 1953- $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic $u Danish Cancer Institute, Strandboulevarden 49, DK-2100 Copenhagen, Denmark $u Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 77, Sweden $7 xx0046271
700    1_
$a Musilek, Kamil $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, Hradec Kralove 500 03, Czech Republic
700    1_
$a Hodny, Zdenek $u Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
773    0_
$w MED00210754 $t ACS pharmacology & translational science $x 2575-9108 $g Roč. 7, č. 9 (2024), s. 2755-2783
856    41
$u https://pubmed.ncbi.nlm.nih.gov/39296273 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20241008 $b ABA008
991    __
$a 20250506100631 $b ABA008
999    __
$a ok $b bmc $g 2196380 $s 1229774
BAS    __
$a 3
BAS    __
$a PreBMC-PubMed-not-MEDLINE
BMC    __
$a 2024 $b 7 $c 9 $d 2755-2783 $e 20240812 $i 2575-9108 $m ACS pharmacology & translational science $n ACS Pharmacol Transl Sci $x MED00210754
LZP    __
$a Pubmed-20241008
Zpět

Najít záznam

Citační ukazatele

Pouze přihlášení uživatelé

Možnosti archivace