1. Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.
- Author
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Westaway SM, Preston AG, Barker MD, Brown F, Brown JA, Campbell M, Chung CW, Diallo H, Douault C, Drewes G, Eagle R, Gordon L, Haslam C, Hayhow TG, Humphreys PG, Joberty G, Katso R, Kruidenier L, Leveridge M, Liddle J, Mosley J, Muelbaier M, Randle R, Rioja I, Rueger A, Seal GA, Sheppard RJ, Singh O, Taylor J, Thomas P, Thomson D, Wilson DM, Lee K, and Prinjha RK
- Subjects
- Amination, Cell Line, Cell Membrane Permeability, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Histone Demethylases chemistry, Histone Demethylases metabolism, Humans, Jumonji Domain-Containing Histone Demethylases chemistry, Jumonji Domain-Containing Histone Demethylases metabolism, Models, Molecular, Pyridines pharmacokinetics, Pyridines pharmacology, Enzyme Inhibitors chemistry, Histone Demethylases antagonists & inhibitors, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Pyridines chemistry
- 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).
- Published
- 2016
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