2 research outputs found
Interrogating the Druggability of the 2‑Oxoglutarate-Dependent Dioxygenase Target Class by Chemical Proteomics
The 2-oxoglutarate-dependent dioxygenase
target class comprises
around 60 enzymes including several subfamilies with relevance to
human disease, such as the prolyl hydroxylases and the Jumonji-type
lysine demethylases. Current drug discovery approaches are largely
based on small molecule inhibitors targeting the iron/2-oxoglutarate
cofactor binding site. We have devised a chemoproteomics approach
based on a combination of unselective active-site ligands tethered
to beads, enabling affinity capturing of around 40 different dioxygenase
enzymes from human cells. Mass-spectrometry-based quantification of
bead-bound enzymes using a free-ligand competition-binding format
enabled the comprehensive determination of affinities for the cosubstrate
2-oxoglutarate and for oncometabolites such as 2-hydroxyglutarate.
We also profiled a set of representative drug-like inhibitor compounds.
The results indicate that intracellular competition by endogenous
cofactors and high active site similarity present substantial challenges
for drug discovery for this target class
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, IC<sub>50</sub> ≤ 100 nM, in KDM4
family biochemical (RFMS) assays with ≥50-fold selectivity
against KDM6B and activity in a mechanistic KDM4C cell imaging assay
(IC<sub>50</sub> = 6–8 μM). Compounds <b>34</b> and <b>39</b> are also potent inhibitors of KDM5C (JARID1C)
(RFMS IC<sub>50</sub> = 100–125 nM)