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8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors

8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors
8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

Caco-2 Cells, Cell Membrane Permeability, Enzyme Inhibitors, Humans, Jumonji Domain-Containing Histone Demethylases, Nuclear Proteins, Pyrimidinones, Repressor Proteins, Journal Article, Research Support, Non-U.S. Gov't
0022-2623
1388-1409
Bavetsias, Vassilios
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Lanigan, Rachel M
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Ruda, Gian Filippo
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Atrash, Butrus
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McLaughlin, Mark G
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Tumber, Anthony
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Mok, N Yi
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Le Bihan, Yann-Vaï
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Dempster, Sally
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Boxall, Katherine J
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Jeganathan, Fiona
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Hatch, Stephanie B
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Savitsky, Pavel
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Velupillai, Srikannathasan
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Krojer, Tobias
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England, Katherine S
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Sejberg, Jimmy
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Thai, Ching
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Donovan, Adam
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Pal, Akos
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Scozzafava, Giuseppe
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Bennett, James M
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Kawamura, Akane
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Johansson, Catrine
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Szykowska, Aleksandra
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Gileadi, Carina
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Burgess-Brown, Nicola A
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von Delft, Frank
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Oppermann, Udo
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Walters, Zoe
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Shipley, Janet
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Raynaud, Florence I
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Westaway, Susan M
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Prinjha, Rab K
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Fedorov, Oleg
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Burke, Rosemary
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Schofield, Christopher J
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Westwood, Isaac M
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Bountra, Chas
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Müller, Susanne
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van Montfort, Rob L M
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Brennan, Paul E
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Blagg, Julian
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Bavetsias, Vassilios
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Lanigan, Rachel M
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Ruda, Gian Filippo
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Atrash, Butrus
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McLaughlin, Mark G
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Tumber, Anthony
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Mok, N Yi
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Le Bihan, Yann-Vaï
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Dempster, Sally
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Boxall, Katherine J
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Jeganathan, Fiona
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Hatch, Stephanie B
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Savitsky, Pavel
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Velupillai, Srikannathasan
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Krojer, Tobias
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England, Katherine S
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Sejberg, Jimmy
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Thai, Ching
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Donovan, Adam
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Pal, Akos
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Scozzafava, Giuseppe
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Bennett, James M
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Kawamura, Akane
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Johansson, Catrine
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Szykowska, Aleksandra
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Gileadi, Carina
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Burgess-Brown, Nicola A
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von Delft, Frank
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Oppermann, Udo
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Walters, Zoe
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Shipley, Janet
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Raynaud, Florence I
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Westaway, Susan M
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Prinjha, Rab K
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Fedorov, Oleg
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Burke, Rosemary
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Schofield, Christopher J
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Westwood, Isaac M
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Bountra, Chas
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Müller, Susanne
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van Montfort, Rob L M
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Brennan, Paul E
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Blagg, Julian
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Bavetsias, Vassilios, Lanigan, Rachel M, Ruda, Gian Filippo, Atrash, Butrus, McLaughlin, Mark G, Tumber, Anthony, Mok, N Yi, Le Bihan, Yann-Vaï, Dempster, Sally, Boxall, Katherine J, Jeganathan, Fiona, Hatch, Stephanie B, Savitsky, Pavel, Velupillai, Srikannathasan, Krojer, Tobias, England, Katherine S, Sejberg, Jimmy, Thai, Ching, Donovan, Adam, Pal, Akos, Scozzafava, Giuseppe, Bennett, James M, Kawamura, Akane, Johansson, Catrine, Szykowska, Aleksandra, Gileadi, Carina, Burgess-Brown, Nicola A, von Delft, Frank, Oppermann, Udo, Walters, Zoe, Shipley, Janet, Raynaud, Florence I, Westaway, Susan M, Prinjha, Rab K, Fedorov, Oleg, Burke, Rosemary, Schofield, Christopher J, Westwood, Isaac M, Bountra, Chas, Müller, Susanne, van Montfort, Rob L M, Brennan, Paul E and Blagg, Julian (2016) 8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors. Journal of Medicinal Chemistry, 59 (4), 1388-1409. (doi:10.1021/acs.jmedchem.5b01635).

Record type: Article

Abstract

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

Full text not available from this repository.

More information

e-pub ahead of print date: 7 January 2016
Published date: 25 February 2016
Keywords: Caco-2 Cells, Cell Membrane Permeability, Enzyme Inhibitors, Humans, Jumonji Domain-Containing Histone Demethylases, Nuclear Proteins, Pyrimidinones, Repressor Proteins, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416325
URI: http://eprints.soton.ac.uk/id/eprint/416325
ISSN: 0022-2623
PURE UUID: 611f4d10-0653-40e7-bbc3-11f0eb56ebee

Catalogue record

Date deposited: 13 Dec 2017 17:30
Last modified: 13 Mar 2019 19:07

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Contributors

Author: Vassilios Bavetsias
Author: Rachel M Lanigan
Author: Gian Filippo Ruda
Author: Butrus Atrash
Author: Mark G McLaughlin
Author: Anthony Tumber
Author: N Yi Mok
Author: Yann-Vaï Le Bihan
Author: Sally Dempster
Author: Katherine J Boxall
Author: Fiona Jeganathan
Author: Stephanie B Hatch
Author: Pavel Savitsky
Author: Srikannathasan Velupillai
Author: Tobias Krojer
Author: Katherine S England
Author: Jimmy Sejberg
Author: Ching Thai
Author: Adam Donovan
Author: Akos Pal
Author: Giuseppe Scozzafava
Author: James M Bennett
Author: Akane Kawamura
Author: Catrine Johansson
Author: Aleksandra Szykowska
Author: Carina Gileadi
Author: Nicola A Burgess-Brown
Author: Frank von Delft
Author: Udo Oppermann
Author: Zoe Walters
Author: Janet Shipley
Author: Florence I Raynaud
Author: Susan M Westaway
Author: Rab K Prinjha
Author: Oleg Fedorov
Author: Rosemary Burke
Author: Christopher J Schofield
Author: Isaac M Westwood
Author: Chas Bountra
Author: Susanne Müller
Author: Rob L M van Montfort
Author: Paul E Brennan
Author: Julian Blagg

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