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

DOI: 10.1042/BCJ20160180 DOI Help

Authors: Peter Hornyak (University of Sussex) , T. Askwith (University of Sussex) , S. Walker (University of Sussex) , E. Komulainen (University of Sussex) , M. Paradowski (University of Sussex) , L. E. Pennicott (University of Sussex) , E. J. Bartlett (University of Sussex) , Nigel Brissett (Genome Damage and Stability Centre, University of Sussex) , A. Raoof (University of Manchester) , M. Watson (University of Manchester) , A. M. Jordan (University of Manchester) , D. J. Ogilvie (University of Manchester) , S. E. Ward (University of Sussex) , J. R. Atack (University of Sussex) , Laurence Pearl (University of Sussex) , K. W. Caldecott (University of Sussex) , Antony W. Oliver (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 473 , PAGES 1869 - 1879

State: Published (Approved)
Published: June 2016
Diamond Proposal Number(s): 10088

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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 01/09/2016 17:07

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