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.
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DOI：
10.1021/acs.jmedchem.5b01635
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发表时间：
2016-02-25
影响因子：
7.3
通讯作者：
Blagg J
中科院分区：
文献类型：
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作者：
Bavetsias V;Lanigan RM;Ruda GF;Atrash B;McLaughlin MG;Tumber A;Mok NY;Le Bihan YV;Dempster S;Boxall KJ;Jeganathan F;Hatch SB;Savitsky P;Velupillai S;Krojer T;England KS;Sejberg J;Thai C;Donovan A;Pal A;Scozzafava G;Bennett JM;Kawamura A;Johansson C;Szykowska A;Gileadi C;Burgess-Brown NA;von Delft F;Oppermann U;Walters Z;Shipley J;Raynaud FI;Westaway SM;Prinjha RK;Fedorov O;Burke R;Schofield CJ;Westwood IM;Bountra C;Müller S;van Montfort RL;Brennan PE;Blagg J
我们发现了N-取代的4-（吡啶-2-基）噻唑-2-胺衍生物，并对其进行了结构优化，得到了一系列有效的JmjC组蛋白N-甲基赖氨酸脱甲基酶（KDM）抑制剂8-（1H-吡唑-3-基）吡啶并[3，4-d]嘧啶-4（3 H）-酮，它们与活性位点的Fe（II）结合。吡唑部分的C4取代允许进入组蛋白肽底物结合位点;构象受限的4-苯基哌啶接头的掺入产生了诸如54 j和54 k的衍生物，其显示出对KDM 4（JMJD 2）和KDM 5（JARID 1）亚家族脱甲基酶的等效活性，对KDM 2、KDM 3和KDM 6亚家族的代表性实例的选择性，Caco-2测定中的细胞渗透性，以及对于54 k，在基于细胞的测定中抑制H3 K9 Me 3和H3 K4 Me 3去甲基化。
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.