Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4‑<i>d</i>]pyrimidin-4(3<i>H</i>)‑one Derivatives

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., <b>1</b>), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido­[3,4-<i>d</i>]­pyrimidin-4­(3<i>H</i>)-one. A number of exemplars such as compound <b>41</b> possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays

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

Optimization of KDM6B (JMJD3) HTS hit <b>12</b> led to the identification of 3-((furan-2-ylmethyl)­amino)­pyridine-4-carboxylic acid <b>34</b> and 3-(((3-methylthiophen-2-yl)­methyl)­amino)­pyridine-4-carboxylic acid <b>39</b> that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds <b>34</b> and <b>39</b> 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 <b>34</b> and <b>39</b> are also potent inhibitors of KDM5C (JARID1C) (RFMS IC₅₀ = 100–125 nM)