5FPL

Crystal structure of human JARID1B in complex with CCT363901

Summary for 5FPL

• Entry DOI: 10.2210/pdb5fpl/pdb
• Related: 5FPU 5FPV
• Descriptor: LYSINE-SPECIFIC DEMETHYLASE 5B, LYSINE-SPECIFIC DEMETHYLASE 5B, ZINC ION, MANGANESE (II) ION, ... (7 entities in total)
• Functional Keywords: oxidoreductase, lysine-specific demethylase 5b
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus : Q9UGL1
• Total number of polymer chains: 1
• Total formula weight: 56004.39

Authors

Srikannathasan, V.,Yann-Vai, L.B.,Nowak, R.,Johansson, C.,Gileadi, C.,von Delft, F.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.,Brennan, P.,Huber, K.,Oppermann, U. (deposition date: 2015-12-02, release date: 2016-01-20, Last modification date: 2024-11-20)

Primary citation

Bavetsias, V.,Lanigan, R.M.,Ruda, G.F.,Atrash, B.,Mclaughlin, M.G.,Tumber, A.,Mok, N.Y.,Le Bihan, Y.,Dempster, S.,Boxall, K.J.,Jeganathan, F.,Hatch, S.B.,Savitsky, P.,Velupillai, S.,Krojer, T.,England, K.S.,Sejberg, J.,Thai, C.,Donovan, A.,Pal, A.,Scozzafava, G.,Bennett, J.M.,Kawamura, A.,Johansson, C.,Szykowska, A.,Gileadi, C.,Burgess-Brown, N.A.,von Delft, F.,Oppermann, U.,Walters, Z.,Shipley, J.,Raynaud, F.I.,Westaway, S.M.,Prinjha, R.K.,Fedorov, O.,Burke, R.,Schofield, C.J.,Westwood, I.M.,Bountra, C.,Muller, S.,Van Montfort, R.L.M.,Brennan, P.E.,Blagg, J.
8-Substituted Pyrido[3,4-D]Pyrimidin-4(3H)-One Derivatives as Potent, Cell Permeable, Kdm4 (Jmjd2) and Kdm5 (Jarid1) Histone Lysine Demethylase Inhibitors.
J.Med.Chem., 59:1388-, 2016

PubMed 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.

PubMed: 26741168
DOI: 10.1021/ACS.JMEDCHEM.5B01635

Experimental method

X-RAY DIFFRACTION (2.35 Å)