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Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C

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Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C. / Leurs, Ulrike; Lohse, Brian; Rand, Kasper Dyrberg; Ming, Shonoi; Riise, Erik Skjold; Cole, Philip A.; Kristensen, Jesper Langgaard; Clausen, Rasmus Prætorius.

In: A C S Chemical Biology, Vol. 9, No. 9, 11.07.2014, p. 2131-2138.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Leurs, U, Lohse, B, Rand, KD, Ming, S, Riise, ES, Cole, PA, Kristensen, JL & Clausen, RP 2014, 'Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C', A C S Chemical Biology, vol. 9, no. 9, pp. 2131-2138. https://doi.org/10.1021/cb500374f

APA

Leurs, U., Lohse, B., Rand, K. D., Ming, S., Riise, E. S., Cole, P. A., ... Clausen, R. P. (2014). Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C. A C S Chemical Biology, 9(9), 2131-2138. https://doi.org/10.1021/cb500374f

Vancouver

Leurs U, Lohse B, Rand KD, Ming S, Riise ES, Cole PA et al. Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C. A C S Chemical Biology. 2014 Jul 11;9(9):2131-2138. https://doi.org/10.1021/cb500374f

Author

Leurs, Ulrike ; Lohse, Brian ; Rand, Kasper Dyrberg ; Ming, Shonoi ; Riise, Erik Skjold ; Cole, Philip A. ; Kristensen, Jesper Langgaard ; Clausen, Rasmus Prætorius. / Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C. In: A C S Chemical Biology. 2014 ; Vol. 9, No. 9. pp. 2131-2138.

Bibtex

@article{ea802a69a08d45eeaf826be4c8cc7b05,
title = "Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C",
abstract = "Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging as the active sites of KDM1A-B and KDM-4A-D histone demethylases, respectively, are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence, or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions, and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.",
author = "Ulrike Leurs and Brian Lohse and Rand, {Kasper Dyrberg} and Shonoi Ming and Riise, {Erik Skjold} and Cole, {Philip A.} and Kristensen, {Jesper Langgaard} and Clausen, {Rasmus Pr{\ae}torius}",
year = "2014",
month = "7",
day = "11",
doi = "10.1021/cb500374f",
language = "English",
volume = "9",
pages = "2131--2138",
journal = "A C S Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "9",

}

RIS

TY - JOUR

T1 - Substrate- and Cofactor-independent Inhibition of Histone Demethylase KDM4C

AU - Leurs, Ulrike

AU - Lohse, Brian

AU - Rand, Kasper Dyrberg

AU - Ming, Shonoi

AU - Riise, Erik Skjold

AU - Cole, Philip A.

AU - Kristensen, Jesper Langgaard

AU - Clausen, Rasmus Prætorius

PY - 2014/7/11

Y1 - 2014/7/11

N2 - Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging as the active sites of KDM1A-B and KDM-4A-D histone demethylases, respectively, are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence, or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions, and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.

AB - Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging as the active sites of KDM1A-B and KDM-4A-D histone demethylases, respectively, are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence, or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions, and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.

U2 - 10.1021/cb500374f

DO - 10.1021/cb500374f

M3 - Journal article

VL - 9

SP - 2131

EP - 2138

JO - A C S Chemical Biology

T2 - A C S Chemical Biology

JF - A C S Chemical Biology

SN - 1554-8929

IS - 9

ER -

ID: 118821637