4 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
Discovery of Tetrahydropyrazolopyridine as Sphingosine 1‑Phosphate Receptor 3 (S1P<sub>3</sub>)‑Sparing S1P<sub>1</sub> Agonists Active at Low Oral Doses
FTY720 is the first oral small molecule
approved for the treatment
of people suffering from relapsing–remitting multiple sclerosis.
It is a potent agonist of the S1P<sub>1</sub> receptor, but its lack
of selectivity against the S1P<sub>3</sub> receptor has been linked
to most of the cardiovascular side effects observed in the clinic.
These findings have triggered intensive efforts toward the identification
of a second generation of S1P<sub>3</sub>-sparing S1P<sub>1</sub> agonists.
We have recently disclosed a series of orally active tetrahydroisoquinoline
(THIQ) compounds matching these criteria. In this paper we describe
how we defined and implemented a strategy aiming at the discovery
of selective structurally distinct follow-up agonists. This effort
culminated with the identification of a series of orally active tetrahydropyrazolopyridines
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, 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)