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dc.contributor.authorRaoof, Ali
dc.contributor.authorDepledge, Paul
dc.contributor.authorHamilton, Niall M
dc.contributor.authorHamilton, Nicola S
dc.contributor.authorHitchin, James R
dc.contributor.authorHopkins, Gemma V
dc.contributor.authorJordan, Allan M
dc.contributor.authorMaguire, Laura A
dc.contributor.authorMcGonagle, Alison E
dc.contributor.authorMould, Daniel P
dc.contributor.authorRushbrooke, M
dc.contributor.authorSmall, Helen F
dc.contributor.authorSmith, Kate M
dc.contributor.authorThomson, Graeme J
dc.contributor.authorTurlais, F
dc.contributor.authorWaddell, Ian D
dc.contributor.authorWaszkowycz, Bohdan
dc.contributor.authorWatson, Amanda J
dc.contributor.authorOgilvie, Donald J
dc.date.accessioned2013-08-30T13:06:40Z
dc.date.available2013-08-30T13:06:40Z
dc.date.issued2013-08-22
dc.identifier.citationToxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II. 2013, 56 (16):6352-70 J Med Chemen_GB
dc.identifier.issn1520-4804
dc.identifier.pmid23859074
dc.identifier.doi10.1021/jm400568p
dc.identifier.urihttp://hdl.handle.net/10541/300423
dc.description.abstractThe 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.
dc.language.isoenen
dc.rightsArchived with thanks to Journal of medicinal chemistryen_GB
dc.titleToxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Drug Discovery Unit, Paterson Institute for Cancer Research, University of Manchester , Wilmslow Road, Manchester M20 4BX, U.K.en_GB
dc.identifier.journalJournal of Medicinal Chemistryen_GB
html.description.abstractThe 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.


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