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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F24%3A50021644" target="_blank" >RIV/62690094:18470/24:50021644 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/24:00598575 RIV/00216208:11110/24:10483744 RIV/00179906:_____/24:10483744

Result on the web

<a href="https://pubs.acs.org/doi/10.1021/acsptsci.4c00190" target="_blank" >https://pubs.acs.org/doi/10.1021/acsptsci.4c00190</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsptsci.4c00190" target="_blank" >10.1021/acsptsci.4c00190</a>

Result language

angličtina

Original language name

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

Original language description

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. © 2024 The Authors. Published by American Chemical Society

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

ACS pharmacology and translational science

ISSN

2575-9108

e-ISSN

2575-9108

Volume of the periodical

7

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

29

Pages from-to

2755-2783

UT code for WoS article

001291121200001

EID of the result in the Scopus database

2-s2.0-85201157560