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Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
Version 2 2023-06-12, 06:38
Version 1 2023-06-09, 01:02
journal contribution
posted on 2023-06-12, 06:38 authored by Peter Hornyak, Trevor Askwith, Sarah Walker, Emilia KomulainenEmilia 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 PearlLaurence Pearl, Keith CaldecottKeith Caldecott, Antony OliverAntony OliverTDP2 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.
Funding
Non-homologous End-Joining Protein Complexes and Genome Stability; G1305; CANCER RESEARCH UK; C6563/A16771
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discov; G0891; CANCER RESEARCH UK; C302/A14532
History
Publication status
- Published
File Version
- Published version
Journal
Biochemical JournalISSN
0264-6021Publisher
Portland PressExternal DOI
Issue
13Volume
473Page range
1869-1879Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-04-26First Open Access (FOA) Date
2017-03-29First Compliant Deposit (FCD) Date
2016-04-26Usage metrics
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