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

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5′-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of...

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Autores principales: 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., Oliver, Antony W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925160/
https://www.ncbi.nlm.nih.gov/pubmed/27099339
http://dx.doi.org/10.1042/BCJ20160180
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author 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.
Oliver, Antony W.
author_facet 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.
Oliver, Antony W.
author_sort Hornyak, Peter
collection PubMed
description Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5′-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). 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 high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanized’ 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.
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spelling pubmed-49251602016-07-12 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. Oliver, Antony W. Biochem J Research Articles Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5′-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). 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 high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanized’ 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. Portland Press Ltd. 2016-06-28 2016-07-01 /pmc/articles/PMC4925160/ /pubmed/27099339 http://dx.doi.org/10.1042/BCJ20160180 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
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.
Oliver, Antony W.
Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title_full Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title_fullStr Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title_full_unstemmed Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title_short Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2
title_sort mode of action of dna-competitive small molecule inhibitors of tyrosyl dna phosphodiesterase 2
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925160/
https://www.ncbi.nlm.nih.gov/pubmed/27099339
http://dx.doi.org/10.1042/BCJ20160180
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