5F2S

Crystal structure of human KDM4A in complex with compound 15

5F2S の概要

• エントリーDOI: 10.2210/pdb5f2s/pdb
• 分子名称: Lysine-specific demethylase 4A, ZINC ION, 2-(2-azanyl-1,3-thiazol-4-yl)pyridine-4-carboxylic acid, ... (7 entities in total)
• 機能のキーワード: epigenetics, demethylase, inhibitor, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : O75164
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 171471.18

構造登録者

Le Bihan, Y.-V.,Dempster, S.,Westwood, I.M.,van Montfort, R.L.M. (登録日: 2015-12-02, 公開日: 2016-01-20, 最終更新日: 2024-01-10)

主引用文献

Bavetsias, V.,Lanigan, R.M.,Ruda, G.F.,Atrash, B.,McLaughlin, M.G.,Tumber, A.,Mok, N.Y.,Le Bihan, Y.V.,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.,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., 59:1388-1409, 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

実験手法

X-RAY DIFFRACTION (2.08 Å)