Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II
| Autor: | Alison E. McGonagle, Graeme J. Thomson, Paul Depledge, Gemma Hopkins, Bohdan Waszkowycz, Mathew Rushbrooke, Nicola Hamilton, Allan M. Jordan, Kate M. Smith, James R. Hitchin, Daniel P. Mould, Helen F. Small, Fabrice Turlais, Ian D. Waddell, Amanda J. Watson, Laura A. Maguire, Donald J. Ogilvie, Niall M. Hamilton, Ali Raoof |
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| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
Toxoflavin biology Phosphoric Diester Hydrolases Triazines DNA damage Topoisomerase Pyrimidinones Pharmacology Structure-Activity Relationship chemistry.chemical_compound Enzyme chemistry Biochemistry Drug Discovery biology.protein Topoisomerase II Inhibitors Molecular Medicine Structure–activity relationship Phosphodiesterase 2 Topoisomerase-II Inhibitor Drug metabolism |
| Zdroj: | Journal of Medicinal Chemistry. 56:6352-6370 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400568p |
| Popis: | The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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