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Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site

Research output: Contribution to Journal/Magazine › Review article › peer-review

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Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. / Exell, Jack C.; Thompson, Mark J.; Finger, L. David et al.
In: Nature Chemical Biology, Vol. 12, No. 10, 10.2016, p. 815-821.

Research output: Contribution to Journal/Magazine › Review article › peer-review

Harvard

Exell, JC, Thompson, MJ, Finger, LD, Shaw, SJ, Debreczeni, J, Ward, TA, McWhirter, C, Siöberg, CLB, Molina, DM, Abbott, WM, Jones, CD, Nissink, JWM, Durant, ST & Grasby, JA 2016, 'Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site', Nature Chemical Biology, vol. 12, no. 10, pp. 815-821. https://doi.org/10.1038/nchembio.2148

APA

Exell, J. C., Thompson, M. J., Finger, L. D., Shaw, S. J., Debreczeni, J., Ward, T. A., McWhirter, C., Siöberg, C. L. B., Molina, D. M., Abbott, W. M., Jones, C. D., Nissink, J. W. M., Durant, S. T., & Grasby, J. A. (2016). Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nature Chemical Biology, 12(10), 815-821. https://doi.org/10.1038/nchembio.2148

Vancouver

Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA et al. Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nature Chemical Biology. 2016 Oct;12(10):815-821. Epub 2016 Aug 15. doi: 10.1038/nchembio.2148

Author

Exell, Jack C. ; Thompson, Mark J. ; Finger, L. David et al. / Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. In: Nature Chemical Biology. 2016 ; Vol. 12, No. 10. pp. 815-821.

Bibtex

@article{15eb2ef6977c4953aa4b9d24057ef5bc,
title = "Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site",
abstract = "The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC 50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC 50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.",
author = "Exell, {Jack C.} and Thompson, {Mark J.} and Finger, {L. David} and Shaw, {Steven J.} and Judit Debreczeni and Ward, {Thomas A.} and Claire McWhirter and Si{\"o}berg, {Catrine L.B.} and Molina, {Daniel Martinez} and Abbott, {W. Mark} and Jones, {Clifford D.} and Nissink, {J. Willem M.} and Durant, {Stephen T.} and Grasby, {Jane A.}",
year = "2016",
month = oct,
doi = "10.1038/nchembio.2148",
language = "English",
volume = "12",
pages = "815--821",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "10",

}

RIS

TY - JOUR

T1 - Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site

AU - Exell, Jack C.

AU - Thompson, Mark J.

AU - Finger, L. David

AU - Shaw, Steven J.

AU - Debreczeni, Judit

AU - Ward, Thomas A.

AU - McWhirter, Claire

AU - Siöberg, Catrine L.B.

AU - Molina, Daniel Martinez

AU - Abbott, W. Mark

AU - Jones, Clifford D.

AU - Nissink, J. Willem M.

AU - Durant, Stephen T.

AU - Grasby, Jane A.

PY - 2016/10

Y1 - 2016/10

N2 - The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC 50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC 50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.

AB - The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC 50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC 50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.

U2 - 10.1038/nchembio.2148

DO - 10.1038/nchembio.2148

M3 - Review article

C2 - 27526030

AN - SCOPUS:84982162361

VL - 12

SP - 815

EP - 821

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 10

ER -