Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

Ali Raoof; Paul Depledge; Niall M Hamilton; Nicola S Hamilton; James R Hitchin; Gemma V Hopkins; Allan M Jordan; Laura A Maguire; Alison E McGonagle; Daniel P Mould; Mathew Rushbrooke; Helen F Small; Kate M Smith; Graeme J Thomson; Fabrice Turlais; Ian D Waddell; Bohdan Waszkowycz; Amanda J Watson; Donald J Ogilvie

doi:10.1021/jm400568p

Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

Ali Raoof, Paul Depledge, Niall M Hamilton, Nicola S Hamilton, James R Hitchin, Gemma V Hopkins, Allan M Jordan, Laura A Maguire, Alison E McGonagle, Daniel P Mould, Mathew Rushbrooke, Helen F Small, Kate M Smith, Graeme J Thomson, Fabrice Turlais, Ian D Waddell, Bohdan Waszkowycz, Amanda J Watson, Donald J Ogilvie

Research output: Contribution to journal › Article › peer-review

Abstract

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge. © 2013 American Chemical Society.

Original language	English
Pages (from-to)	6352-6370
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	16
DOIs	https://doi.org/10.1021/jm400568p https://doi.org/10.1021/jm400568p
Publication status	Published - 22 Aug 2013

Keywords

Phosphoric Diester Hydrolases
Pyrimidinones
Structure-Activity Relationship
Topoisomerase II Inhibitors
Triazines

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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Raoof, A., Depledge, P., Hamilton, N. M., Hamilton, N. S., Hitchin, J. R., Hopkins, G. V., Jordan, A. M., Maguire, L. A., McGonagle, A. E., Mould, D. P., Rushbrooke, M., Small, H. F., Smith, K. M., Thomson, G. J., Turlais, F., Waddell, I. D., Waszkowycz, B., Watson, A. J., & Ogilvie, D. J. (2013). Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II. Journal of Medicinal Chemistry, 56(16), 6352-6370. https://doi.org/10.1021/jm400568p, https://doi.org/10.1021/jm400568p

@article{aee3ea803964430eb54789981870f408,

title = "Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II",

abstract = "The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge. {\textcopyright} 2013 American Chemical Society.",

keywords = "Phosphoric Diester Hydrolases, Pyrimidinones, Structure-Activity Relationship, Topoisomerase II Inhibitors, Triazines",

author = "Ali Raoof and Paul Depledge and Hamilton, {Niall M} and Hamilton, {Nicola S} and Hitchin, {James R} and Hopkins, {Gemma V} and Jordan, {Allan M} and Maguire, {Laura A} and McGonagle, {Alison E} and Mould, {Daniel P} and Mathew Rushbrooke and Small, {Helen F} and Smith, {Kate M} and Thomson, {Graeme J} and Fabrice Turlais and Waddell, {Ian D} and Bohdan Waszkowycz and Watson, {Amanda J} and Ogilvie, {Donald J}",

year = "2013",

month = aug,

day = "22",

doi = "10.1021/jm400568p",

language = "English",

volume = "56",

pages = "6352--6370",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Raoof, A, Depledge, P, Hamilton, NM, Hamilton, NS, Hitchin, JR, Hopkins, GV, Jordan, AM, Maguire, LA, McGonagle, AE, Mould, DP, Rushbrooke, M, Small, HF, Smith, KM, Thomson, GJ, Turlais, F, Waddell, ID, Waszkowycz, B, Watson, AJ & Ogilvie, DJ 2013, 'Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II', Journal of Medicinal Chemistry, vol. 56, no. 16, pp. 6352-6370. https://doi.org/10.1021/jm400568p, https://doi.org/10.1021/jm400568p

TY - JOUR

T1 - Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

AU - Raoof, Ali

AU - Depledge, Paul

AU - Hamilton, Niall M

AU - Hamilton, Nicola S

AU - Hitchin, James R

AU - Hopkins, Gemma V

AU - Jordan, Allan M

AU - Maguire, Laura A

AU - McGonagle, Alison E

AU - Mould, Daniel P

AU - Rushbrooke, Mathew

AU - Small, Helen F

AU - Smith, Kate M

AU - Thomson, Graeme J

AU - Turlais, Fabrice

AU - Waddell, Ian D

AU - Waszkowycz, Bohdan

AU - Watson, Amanda J

AU - Ogilvie, Donald J

PY - 2013/8/22

Y1 - 2013/8/22

N2 - The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge. © 2013 American Chemical Society.

AB - The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge. © 2013 American Chemical Society.

KW - Phosphoric Diester Hydrolases

KW - Pyrimidinones

KW - Structure-Activity Relationship

KW - Topoisomerase II Inhibitors

KW - Triazines

U2 - 10.1021/jm400568p

DO - 10.1021/jm400568p

M3 - Article

C2 - 23859074

SN - 0022-2623

VL - 56

SP - 6352

EP - 6370

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 16

ER -

Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

Abstract

Keywords

Research Beacons, Institutes and Platforms

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