title: Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II.
abstract: 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.
authors.affiliation: Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, U.K. araoof@picr.man.ac.uk.
authors.forename: Ali
authors.initials: A
authors.lastname: Raoof
authors.forename: Paul
authors.initials: P
authors.lastname: Depledge
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Hamilton
authors.forename: James R
authors.initials: JR
authors.lastname: Hitchin
authors.forename: Gemma V
authors.initials: GV
authors.lastname: Hopkins
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maguire
authors.forename: Alison E
authors.initials: AE
authors.lastname: McGonagle
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Mould
authors.forename: Mathew
authors.initials: M
authors.lastname: Rushbrooke
authors.forename: Helen F
authors.initials: HF
authors.lastname: Small
authors.forename: Kate M
authors.initials: KM
authors.lastname: Smith
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Thomson
authors.forename: Fabrice
authors.initials: F
authors.lastname: Turlais
authors.forename: Ian D
authors.initials: ID
authors.lastname: Waddell
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
mesh_terms: D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011744:Pyrimidinones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D011744:Pyrimidinones; D059005:Topoisomerase II Inhibitors; D014227:Triazines; C009570:toxoflavin; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase