dc.contributor.author | Bavetsias, V | |
dc.contributor.author | Lanigan, RM | |
dc.contributor.author | Ruda, GF | |
dc.contributor.author | Atrash, B | |
dc.contributor.author | McLaughlin, MG | |
dc.contributor.author | Tumber, A | |
dc.contributor.author | Mok, NY | |
dc.contributor.author | Le Bihan, Y-V | |
dc.contributor.author | Dempster, S | |
dc.contributor.author | Boxall, KJ | |
dc.contributor.author | Jeganathan, F | |
dc.contributor.author | Hatch, SB | |
dc.contributor.author | Savitsky, P | |
dc.contributor.author | Velupillai, S | |
dc.contributor.author | Krojer, T | |
dc.contributor.author | England, KS | |
dc.contributor.author | Sejberg, J | |
dc.contributor.author | Thai, C | |
dc.contributor.author | Donovan, A | |
dc.contributor.author | Pal, A | |
dc.contributor.author | Scozzafava, G | |
dc.contributor.author | Bennett, JM | |
dc.contributor.author | Kawamura, A | |
dc.contributor.author | Johansson, C | |
dc.contributor.author | Szykowska, A | |
dc.contributor.author | Gileadi, C | |
dc.contributor.author | Burgess-Brown, NA | |
dc.contributor.author | von Delft, F | |
dc.contributor.author | Oppermann, U | |
dc.contributor.author | Walters, Z | |
dc.contributor.author | Shipley, J | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Westaway, SM | |
dc.contributor.author | Prinjha, RK | |
dc.contributor.author | Fedorov, O | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Schofield, CJ | |
dc.contributor.author | Westwood, IM | |
dc.contributor.author | Bountra, C | |
dc.contributor.author | Müller, S | |
dc.contributor.author | van Montfort, RLM | |
dc.contributor.author | Brennan, PE | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2020-06-22T15:47:39Z | |
dc.date.issued | 2016-02-25 | |
dc.identifier.citation | Journal of medicinal chemistry, 2016, 59 (4), pp. 1388 - 1409 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3767 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.5b01635 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1388 - 1409 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Caco-2 Cells | |
dc.subject | Humans | |
dc.subject | Pyrimidinones | |
dc.subject | Nuclear Proteins | |
dc.subject | Repressor Proteins | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Cell Membrane Permeability | |
dc.subject | Jumonji Domain-Containing Histone Demethylases | |
dc.title | 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.5b01635 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-02 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 4 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.volume | 59 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Sarcoma Molecular Pathology | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Bavetsias, Vassilios | |
dc.contributor.icrauthor | Le Bihan, Yann-Vai | |
dc.contributor.icrauthor | Pal, Akos | |
dc.contributor.icrauthor | Shipley, Janet | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Van Montfort, Robert | |