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Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II
journal contribution
posted on 2013-08-22, 00:00 authored by Ali Raoof, Paul Depledge, Niall
M. Hamilton, Nicola S. Hamilton, James R. Hitchin, Gemma V. Hopkins, Allan M. Jordan, Laura A. Maguire, Alison E. McGonagle, Daniel P. Mould, Mathew Rushbrooke, Helen F. Small, Kate M. Smith, Graeme J. Thomson, Fabrice Turlais, Ian D. Waddell, Bohdan Waszkowycz, Amanda J. Watson, Donald J. OgilvieThe 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.