Abstract
Studies on the inhibition of the human 2‐oxoglutarate dependent oxygenase JMJD6, which is a cancer target, by 2‐oxoglutarate mimics / competitors, including human drugs, drug candidates, and metabolites relevant to cancer are described. JMJD6 assays employed NMR to monitor inhibitor binding and use of mass spectrometry to monitor JMJD6‐catalysed lysine hydroxylation. Notably, some clinically applied prolyl hydroxylase inhibitors also inhibit JMJD6. The results will help enable the development of inhibitors selective for human oxygenases, including JMJD6.
Highlights
Studies on the inhibition of the human 2-oxoglutarate dependent oxygenase JMJD6, which is a cancer target, by 2oxoglutarate mimics / competitors, including human drugs, drug candidates, and metabolites relevant to cancer are described
Erythropoietin levels are regulated by hypoxia inducible factors (HIFs) and the prolyl hydroxylases (PHDs) are current drug targets for treatment of hypoxia related diseases such as anaemia.[6,7,8]
PHD inhibitors have been approved for clinical use in China and Japan, but in some cases cardiac effects on heart function have been reported, as was the case in earlier work with collagen prolyl hydroxylase inhibitors.[7,8,9]
Summary
The 8-hydroxyquinoline derivatives 5-carboxy-8-hydroxyquinoline (IOX1) and 2, pyridine derivatives pyridine-2,4-dicarboxylate (2,4-PDCA) and 2,2’-bipyridine-4,4’-dicarboxylate (2,4-BPDCA), and the PHD inhibitors GSK1278863, Vadadustat and AKB-6899 were the most potent identified inhibitors (IC50 values < 15 μM) (Table 1). We investigated whether the inhibitors compete for binding to JMJD6Δ363-403, using 1H NMR to investigate the extent to which they displace 2OG from the JMJD6Δ363-403.Zn(II).2OG complex, initially with a fixed inhibitor concentration (Figure S6).[21,22] The results imply the analysed inhibitors compete with 2OG and broadly, though not fully, correlate with the IC50 values; in the initial screen succinate, fumarate, 2,4-PDCA, 2,4-BPDCA, Vadadustat and AKB-6899 most efficiently displaced 2OG of the tested compounds. Apparent binding constant KDapp values for six selected inhibitors were determined by NMR with values of 159 μM / succinate, 109 μM / fumarate, 6 μM / 2,4-PDCA,.
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