Topoisomerase I Inhibitor Development in Cancer Therapy

Topoisomerase I is a nuclear enzyme that relieves torsional stress in DNA by inducing transient single-strand breaks and re-ligation, a process essential for replication and transcription. Inhibitors of this enzyme convert it into a cellular poison, stabilising the cleavable complex and triggering DNA damage that preferentially kills rapidly dividing cancer cells. The prototypical camptothecin and its derivatives, such as topotecan and irinotecan, have formed the backbone of several chemotherapy regimens, yet their clinical utility is hampered by poor stability, off-target toxicity and the emergence of drug resistance. To overcome these limitations, research has diversified into non-camptothecin scaffolds, novel synthetic analogues and targeted delivery systems. Advanced molecular modelling and virtual screening have identified nitrogenated derivatives of natural compounds with enhanced binding affinity and favourable pharmacokinetic profiles. Concurrently, catalytic inhibitors that prevent complex formation and innovative screening platforms have streamlined lead identification. Resistance mechanisms—ranging from topoisomerase I mutations and altered expression to epigenetic reprogramming—have prompted combination strategies, pairing topoisomerase I inhibitors with epigenetic modulators or DNA-repair antagonists to restore sensitivity. Collectively, these efforts aim to expand the therapeutic window, reduce adverse effects and address heterogeneity in patient response, charting a path towards more personalised and effective interventions.

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Topoisomerase I Inhibitor Development in Cancer Therapy publication trend

The graph below shows the total number of articles in topoisomerase i inhibitor development in cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Topoisomerase I: An enzyme that relaxes supercoiled DNA by creating transient single-strand breaks and re-joining them during replication and transcription.

Cleavable complex: A transient intermediate in which topoisomerase I is covalently linked to DNA; stabilisation by inhibitors leads to DNA damage.

Camptothecin: A natural alkaloid that traps the topoisomerase I–DNA complex, serving as the prototype for clinically used inhibitors.

ADMET: An acronym for absorption, distribution, metabolism, excretion and toxicity, key properties assessed during drug development.

Epigenetic modifications: Heritable chemical changes to DNA or histone proteins—such as methylation and acetylation—that regulate gene expression without altering the DNA sequence.

References

1. Unveiling the Anticancer Potential: Computational Exploration of Nitrogenated Derivatives of (+)-Pancratistatin as Topoisomerase I Inhibitors. International Journal of Molecular Sciences (2024).
2. Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds. Pharmaceuticals (2023).
3. Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors. Annals of Medicine (2023).