Repurposing MK0873 as a non-covalent hTERT-Targeting compound: a proof of concept study

Vollständiger Abstract

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Telomerase is a key regulator of both cellular immortality and aging, making it an attractive target for cancer therapy and age associated pathologies. Its clinical exploitation has been limited by structural complexity and challenges in achieving specificity. Recent structural insights into human telomerase reverse transcriptase (hTERT) have enabled the identification of selective inhibitors. Here, we repurposed MK0873, a PDE4 inhibitor previously evaluated in Phase II clinical trials for rheumatoid arthritis and COPD, as a non covalent telomerase targeting agent. In silico docking and molecular dynamics simulations predicted stable binding of MK0873 to hTERT, distinct from the covalent interaction of BIBR1532. Analysis of neuroblastoma datasets revealed that high TERT expression correlates with poorer survival, independent of MYCN amplification. MK0873 reduced proliferation of hTERT positive cells, promoted cellular senescence and decreased relative telomere length, whereas ALT positive cells exhibited minimal response, supporting selective activity in telomerase dependent cellular models. Importantly, direct biochemical assessment using the Telomeric Repeat Amplification Protocol assay demonstrated a significant reduction in telomerase activity following MK0873 treatment, providing experimental evidence that complements the computational predictions and cellular phenotypes observed in this study. Although the magnitude of telomerase inhibition was lower than that of the reference inhibitor BIBR1532 under identical experimental conditions, the combined computational, biochemical and cellular findings consistently support hTERT as a relevant molecular target of MK0873. Collectively, these results provide proof of concept evidence that MK0873 represents a promising lead scaffold for non covalent targeting of hTERT. While additional studies are required to further define cellular target engagement, distinguish potential PDE4 dependent effects and optimize inhibitory potency. Current work establishes a foundation for the continued development of MK0873 derived compounds as potential telomerase targeted anticancer therapeutics.