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

Peter Hornyak, Trevor Askwith, Sarah Walker, Emilia Komulainen, Michael Paradowski, Lewis E. Pennicott, Edward J. Bartlett, Nigel Brissett, Ali Raoof, Mandy Watson, Allan M. Jordan, Donald J. Ogilvie, Simon E. Ward, John R. Atack, Laurence H. Pearl, Keith W. Caldecott, Antony W. Oliver

Research output: Contribution to journalArticle

Abstract

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). 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 high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a 'humanized' 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.
Original languageEnglish
Pages (from-to)1869–1879
JournalBiochemical Journal
Volume473
Issue number13
DOIs
Publication statusPublished - 20 Apr 2016

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