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

Journal of Medicinal Chemistry
Susan M WestawayRab K Prinjha

Abstract

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).

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Citations

Oct 13, 2016·Expert Opinion on Therapeutic Patents·Florian Thaler, Ciro Mercurio
Mar 25, 2017·Chemical Reviews·H Ümit KaniskanJian Jin
Apr 14, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Hongzhi LinHaopeng Sun
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Dec 1, 2019·Bioorganic & Medicinal Chemistry·Vatroslav LetfusSanja Koštrun
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Nov 6, 2018·Journal of Medicinal Chemistry·John R HortonXiaodong Cheng
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