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Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-01-15 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01537
Susan M. Westaway 1 , Alex G. S. Preston 1 , Michael D. Barker 1 , Fiona Brown 2 , Jack A. Brown 1 , Matthew Campbell 1 , Chun-wa Chung 2 , Hawa Diallo 1 , Clement Douault 1 , Gerard Drewes 3 , Robert Eagle 2 , Laurie Gordon 2 , Carl Haslam 2 , Thomas G. Hayhow 1 , Philip G. Humphreys 1 , Gerard Joberty 3 , Roy Katso 2 , Laurens Kruidenier 1 , Melanie Leveridge 2 , John Liddle 1 , Julie Mosley 2 , Marcel Muelbaier 3 , Rebecca Randle 2 , Inma Rioja 1 , Anne Rueger 3 , Gail A. Seal 1 , Robert J. Sheppard 1 , Onkar Singh 2 , Joanna Taylor 2 , Pamela Thomas 2 , Douglas Thomson 3 , David M. Wilson 1 , Kevin Lee 1 , Rab K. Prinjha 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-01-15 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01537
Susan M. Westaway 1 , Alex G. S. Preston 1 , Michael D. Barker 1 , Fiona Brown 2 , Jack A. Brown 1 , Matthew Campbell 1 , Chun-wa Chung 2 , Hawa Diallo 1 , Clement Douault 1 , Gerard Drewes 3 , Robert Eagle 2 , Laurie Gordon 2 , Carl Haslam 2 , Thomas G. Hayhow 1 , Philip G. Humphreys 1 , Gerard Joberty 3 , Roy Katso 2 , Laurens Kruidenier 1 , Melanie Leveridge 2 , John Liddle 1 , Julie Mosley 2 , Marcel Muelbaier 3 , Rebecca Randle 2 , Inma Rioja 1 , Anne Rueger 3 , Gail A. Seal 1 , Robert J. Sheppard 1 , Onkar Singh 2 , Joanna Taylor 2 , Pamela Thomas 2 , Douglas Thomson 3 , David M. Wilson 1 , Kevin Lee 1 , Rab K. Prinjha 1
Affiliation
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Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6–8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100–125 nM).
中文翻译：
组蛋白赖氨酸脱甲基酶的KDM4和KDM5家族的细胞渗透抑制剂。1. 3-氨基-4-吡啶羧酸酯衍生物
优化KDM6B（JMJD3）HTS 12命中率导致了3-（（呋喃-2-基甲基）氨基）吡啶-4-羧酸34和3-（（（3-甲基噻吩-2-基）甲基）氨基的鉴定）吡啶-4-羧酸39是组蛋白赖氨酸脱甲基酶KDM4（JMJD2）家族的抑制剂。化合物34和39具有活性，IC 50 ≤100nm时，在家庭KDM4生化（RFMS）与一种机械KDM4C细胞成像测定法针对KDM6B≥50倍的选择性和活性的测定法（IC 50 = 6-8微米）。化合物34和39也是KDM5C（JARID1C）的有效抑制剂（RFMS IC 50 = 100–125 nM）。
更新日期：2016-01-15
中文翻译：
组蛋白赖氨酸脱甲基酶的KDM4和KDM5家族的细胞渗透抑制剂。1. 3-氨基-4-吡啶羧酸酯衍生物
优化KDM6B（JMJD3）HTS 12命中率导致了3-（（呋喃-2-基甲基）氨基）吡啶-4-羧酸34和3-（（（3-甲基噻吩-2-基）甲基）氨基的鉴定）吡啶-4-羧酸39是组蛋白赖氨酸脱甲基酶KDM4（JMJD2）家族的抑制剂。化合物34和39具有活性，IC 50 ≤100nm时，在家庭KDM4生化（RFMS）与一种机械KDM4C细胞成像测定法针对KDM6B≥50倍的选择性和活性的测定法（IC 50 = 6-8微米）。化合物34和39也是KDM5C（JARID1C）的有效抑制剂（RFMS IC 50 = 100–125 nM）。
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