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

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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 Oliver
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.

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 Journal

ISSN

0264-6021

Publisher

Portland Press

Issue

13

Volume

473

Page range

1869-1879

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-04-26

First Open Access (FOA) Date

2017-03-29

First Compliant Deposit (FCD) Date

2016-04-26

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