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Background <p>Cellular senescence is a stress-induced state characterized by irreversible cell cycle arrest. Senescent cells accumulate during aging and contribute to age-related diseases, including neurodegeneration, cancer, and type 2 diabetes mellitus. The mTOR signaling pathway plays a critical role in maintaining and regulating senescence-associated features.</p> Methods <p>We employed virtual high-throughput screening and fragment-based design to identify novel small-molecule competitive mTOR kinase inhibitors with favorable physicochemical properties. Six lead compounds (1–6) were selected, and torkinib (7) was synthesized and used as a reference.</p> Results <p>Biochemical and cell-based assays revealed that torkinib and compounds 5 and 6 inhibited mTORC1-mediated phosphorylation of p70 S6K. Compound 5 exhibited cytostatic effects in both non-transformed human cells and glioma cancer cells, with greater sensitivity observed in the latter. Unlike the rapalog temsirolimus, both torkinib and compound 5 suppressed migration in multiple glioblastoma cell lines. Notably, compound 5 induced a transient autophagy flux distinct from that elicited by other tested mTOR inhibitors. Furthermore, compound 5 reduced radiation-induced expression of senescence-associated secretory phenotype (SASP) markers, including IL-1α, IL-6, and IL-8. Additional senomorphic effects included decreased cell size and reduced senescence-associated β-galactosidase activity. In vivo, compound 5 showed slightly higher toxicity than torkinib, likely due to improved solubility.</p> Conclusions <p>Compound 5 demonstrates distinct biological effects compared to torkinib and represents a promising candidate for further development as an mTOR inhibitor targeting both cancer and senescent cells.</p>

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In silico screening, synthesis, and biological evaluation of pyrazolopyrimidine-derived mTOR inhibitors for anticancer and senomorphic effects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • David Rysanek,
  • Zofia Chrienova,
  • Dorota Stary,
  • Marek Bajda,
  • Josef Novak,
  • Pavla Vasicova,
  • Jirina Kroupova,
  • Rudolf Andrys,
  • Adam Skarka,
  • Erika Rousarova,
  • Jan Capek,
  • Tomas Rousar,
  • Zoran Milovanovic,
  • Jelica Grujic-Milanovic,
  • Vesna Jacevic,
  • Jayaprakash N. Kolla,
  • Martin Popr,
  • Dominika Maurencova,
  • Patrik Oleksak,
  • Lukas Fresser,
  • Kamil Kuca,
  • Zdenek Hodny,
  • Eugenie Nepovimova

摘要

Background

Cellular senescence is a stress-induced state characterized by irreversible cell cycle arrest. Senescent cells accumulate during aging and contribute to age-related diseases, including neurodegeneration, cancer, and type 2 diabetes mellitus. The mTOR signaling pathway plays a critical role in maintaining and regulating senescence-associated features.

Methods

We employed virtual high-throughput screening and fragment-based design to identify novel small-molecule competitive mTOR kinase inhibitors with favorable physicochemical properties. Six lead compounds (1–6) were selected, and torkinib (7) was synthesized and used as a reference.

Results

Biochemical and cell-based assays revealed that torkinib and compounds 5 and 6 inhibited mTORC1-mediated phosphorylation of p70 S6K. Compound 5 exhibited cytostatic effects in both non-transformed human cells and glioma cancer cells, with greater sensitivity observed in the latter. Unlike the rapalog temsirolimus, both torkinib and compound 5 suppressed migration in multiple glioblastoma cell lines. Notably, compound 5 induced a transient autophagy flux distinct from that elicited by other tested mTOR inhibitors. Furthermore, compound 5 reduced radiation-induced expression of senescence-associated secretory phenotype (SASP) markers, including IL-1α, IL-6, and IL-8. Additional senomorphic effects included decreased cell size and reduced senescence-associated β-galactosidase activity. In vivo, compound 5 showed slightly higher toxicity than torkinib, likely due to improved solubility.

Conclusions

Compound 5 demonstrates distinct biological effects compared to torkinib and represents a promising candidate for further development as an mTOR inhibitor targeting both cancer and senescent cells.