Human Lysine Demethylase JMJD2D (KDM4D); A Target Enabling Package

<p>There are 4 members of the Lysine Demethylase JMJD2 (KDM4) family. SGC Oxford has expressed, purified and crystallized the catalytic domains of JMJD2A, JMJD2B, JMJD2C and JMJD2D as part of the probe programme. Fragment screening and X-ray crystallography identified a large number of binders, some of which were progressed into a medicinal chemistry programme. Despite significant effort molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p

Human Lysine Demethylase JMJD1B (KDM3B); A Target Enabling Package

<p>There are 3 members of the Lysine Demethylase JMJD1 (KDM3) family, JMJD1A-C. SGC Oxford has expressed, purified and crystallized the catalytic domains of JMJD1A, JMJD1B and JMJD1C as part of the probe programme. Fragment screening and X-ray crystallography identified a large number of binders, some of which were progressed into a medicinal chemistry programme. Despite significant effort molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p

Human Lysine Demethylase JMJD2D (KDM4D); A Target Enabling Package

<p>There are 4 members of the Lysine Demethylase JMJD2 (KDM4) family. SGC Oxford has expressed, purified and crystallized the catalytic domains of JMJD2A, JMJD2B, JMJD2C and JMJD2D as part of the probe programme. Fragment screening and X-ray crystallography identified a large number of binders, some of which were progressed into a medicinal chemistry programme. Despite significant effort molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p

8‑Substituted Pyrido[3,4‑<i>d</i>]pyrimidin-4(3<i>H</i>)‑one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

We report the discovery of <i>N</i>-substituted 4-(pyridin-2-yl)­thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1<i>H</i>-pyrazol-3-yl)­pyrido­[3,4-<i>d</i>]­pyrimidin-4­(3<i>H</i>)-ones, a series of potent JmjC histone <i>N</i>-methyl lysine demethylase (KDM) inhibitors which bind to Fe­(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as <b>54j</b> and <b>54k</b> which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for <b>54k</b>, inhibition of H3K9Me₃ and H3K4Me₃ demethylation in a cell-based assay

8‑Substituted Pyrido[3,4‑<i>d</i>]pyrimidin-4(3<i>H</i>)‑one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

We report the discovery of <i>N</i>-substituted 4-(pyridin-2-yl)­thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1<i>H</i>-pyrazol-3-yl)­pyrido­[3,4-<i>d</i>]­pyrimidin-4­(3<i>H</i>)-ones, a series of potent JmjC histone <i>N</i>-methyl lysine demethylase (KDM) inhibitors which bind to Fe­(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as <b>54j</b> and <b>54k</b> which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for <b>54k</b>, inhibition of H3K9Me₃ and H3K4Me₃ demethylation in a cell-based assay