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

Hornyak, Peter, Askwith, Trevor, Walker, Sarah, Komulainen, Emilia, Paradowski, Michael, Pennicott, Lewis E, Bartlett, Edward J, Brissett, Nigel C, Raoof, Ali, Watson, Mandy, Jordan, Allan M, Ogilvie, Donald J, Ward, Simon E, Atack, John R, Pearl, Laurence H, Caldecott, Keith W and Oliver, Antony W (2016) Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochemical Journal, 473 (13). pp. 1869-1879. ISSN 0264-6021

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
School of Life Sciences > Sussex Centre for Genome Damage and Stability
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Depositing User: Antony Oliver
Date Deposited: 26 Apr 2016 09:20
Last Modified: 18 Aug 2017 09:44
URI: http://sro.sussex.ac.uk/id/eprint/60620

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Project NameSussex Project NumberFunderFunder Ref
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug DiscovG0891CANCER RESEARCH UKC302/A14532
Non-homologous End-Joining Protein Complexes and Genome StabilityG1305CANCER RESEARCH UKC6563/A16771