Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives

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• 作者：Susan M. Westaway ; Alex G. S. Preston ; Michael D. Barker ; Fiona Brown ; Jack A. Brown ; Matthew Campbell ; Chun-wa Chung ; Hawa Diallo ; Clement Douault ; Gerard Drewes ; Robert Eagle ; Laurie Gordon ; Carl Haslam ; Thomas G. Hayhow ; Philip G. Humphreys ; Gerard Joberty ; Roy Katso ; Laurens Kruidenier ; Melanie Leveridge ; John Liddle ; Julie Mosley ; Marcel Muelbaier ; Rebecca Randle ; Inma Rioja ; Anne Rueger ; Gail A. Seal ; Robert J. Sheppard ; Onkar Singh ; Joanna Taylor ; Pamela Thomas ; Douglas Thomson ; David M. Wilson ; Kevin Lee ; Rab K. Prinjha
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1357-1369
• 全文大小：519K
• ISSN：1520-4804

文摘

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).