Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.
Authors
Hornyak, PAskwith, 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
Affiliation
Genome Damage and Stability Centre, University of Sussex, School of Life Sciences, Falmer, BN1 9RQIssue Date
2016-04-20
Metadata
Show full item recordAbstract
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 JJournal
The Biochemical JournalDOI
10.1042/BCJ20160180PubMed ID
27099339Type
ArticleLanguage
enISSN
1470-8728ae974a485f413a2113503eed53cd6c53
10.1042/BCJ20160180
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