Ondrej Novotny
@img.cas.cz
IMG CAS
RESEARCH, TEACHING, or OTHER INTERESTS
Molecular Biology
Scopus Publications
- 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
Patrik Oleksak, David Rysanek, Marketa Vancurova, Pavla Vasicova, Alexandra Urbancokova, Josef Novak, Dominika Maurencova, Pavel Kashmel, Jana Houserova, Romana Mikyskova, Ondrej Novotny, Milan Reinis, Pavel Juda, Miroslav Hons, Jirina Kroupova, David Sedlak, Tetyana Sulimenko, Pavel Draber, Marketa Chlubnova, Eugenie Nepovimova, Kamil Kuca, Miroslav Lisa, Rudolf Andrys, Tereza Kobrlova, Ondrej Soukup, Jiri Janousek, Lukas Prchal, Jiri Bartek, Kamil Musilek, Zdenek Hodny
ACS Pharmacology and Translational Science, 2024
High Resolution Image Download MS PowerPoint Slide 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. - STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells
Romana Mikyskova, Olena Sapeg, Miroslav Psotka, Ondrej Novotny, Zdeněk Hodny, Sona Balintova, David Malinak, Jana Svobodova, Rudolf Andrys, David Rysanek, Kamil Musilek, Milan Reinis
Molecular Medicine Reports, 2023
Signal transducer and activator of transcription 3 (STAT3) signalling serves an important role in carcinogenesis and cellular senescence, and its inhibition in tumour cells represents an attractive therapeutic target. Premature cellular senescence, a process of permanent proliferative arrest of cells in response to various inducers, such as cytostatic drugs or ionizing radiation, is accompanied by morphological and secretory changes, and by altered susceptibility to chemotherapeutic agents, which can thereby complicate their eradication by cancer therapies. In the present study, the responsiveness of proliferating and docetaxel (DTX)-induced senescent cancer cells to small molecule STAT3 inhibitor Stattic and its analogues was evaluated using tumour cell lines. These agents displayed cytotoxic effects in cell viability assays on both proliferating and senescent murine TRAMP-C2 and TC-1 cells; however, senescent cells were markedly more resistant. Western blot analysis revealed that Stattic and its analogues effectively inhibited constitutive STAT3 phosphorylation in both proliferating and senescent cells. Furthermore, whether the Stattic-derived inhibitor K1836 could affect senescence induction or modulate the phenotype of senescent cells was evaluated. K1836 treatment demonstrated no effect on senescence induction by DTX. However, the K1836 compound significantly modulated secretion of certain cytokines (interleukin-6, growth-regulated oncogene α and monocyte chemoattractant protein-1). In summary, the present study demonstrated differences between proliferating and senescent tumour cells in terms of their susceptibility to STAT3 inhibitors and demonstrated the ability of the new STAT3 inhibitor K1836 to affect the secretion of essential components of the senescence-associated secretory phenotype. The present study may be useful for further development of STAT3 inhibitor-based therapy of cancer or age-related diseases. - Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics
Zofia Chrienova, David Rysanek, Patrik Oleksak, Dorota Stary, Marek Bajda, Milan Reinis, Romana Mikyskova, Ondrej Novotny, Rudolf Andrys, Adam Skarka, Pavla Vasicova, Josef Novak, Martin Valis, Kamil Kuca, Zdenek Hodny, Eugenie Nepovimova
Frontiers in Aging Neuroscience, 2022
To date, the most studied drug in anti-aging research is the mTOR inhibitor – rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation – inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.
