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).
MeSH terms
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Amination
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Cell Line
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Cell Membrane Permeability
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Histone Demethylases / antagonists & inhibitors*
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Histone Demethylases / chemistry
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Histone Demethylases / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
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Jumonji Domain-Containing Histone Demethylases / chemistry
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Models, Molecular
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
Substances
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Enzyme Inhibitors
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KDM4C protein, human
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Pyridines
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM4D protein, human
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KDM5C protein, human
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KDM6B protein, human