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    Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.

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    Authors
    Hornyak, P
    Askwith, T
    Walker, S
    Komulainen, E
    Paradowski, M
    Pennicott, L
    Bartlett, E
    Brissett, N
    Raoof, Ali
    Watson, Mandy
    Jordan, Allan M
    Ogilvie, Donald J
    Ward, S
    Atack, J
    Pearl, L
    Caldecott, K
    Oliver, A
    Show allShow less
    Affiliation
    Genome Damage and Stability Centre, University of Sussex, School of Life Sciences, Falmer, BN1 9RQ
    Issue Date
    2016-04-20
    
    Metadata
    Show full item record
    Abstract
    TDP2 is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II. TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for HTS-screening.  We have gone on to determine crystal structures of these compounds bound to a 'humanised' form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2.
    Citation
    Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. 2016: Biochem J
    Journal
    The Biochemical Journal
    URI
    http://hdl.handle.net/10541/610740
    DOI
    10.1042/BCJ20160180
    PubMed ID
    27099339
    Type
    Article
    Language
    en
    ISSN
    1470-8728
    ae974a485f413a2113503eed53cd6c53
    10.1042/BCJ20160180
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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