Structure‐Activity Relationship and Crystallographic Studies on 4‐Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors

Abstract

are co-founders of a company, ReOx, which aims to exploit basic science discoveries about the hypoxic response for therapeutic benefit.

Reducing Agent‐Mediated Nonenzymatic Conversion of 2‐Oxoglutarate to Succinate: Implications for Oxygenase Assays

“…The Fe II -and 2-oxoglutarate (2OG)-dependent oxygenase superfamily of structurally and mechanistically related enzymes is widely distributed throughout much of biology. [1][2][3][4] Some human 2OG oxygenases are current therapeutic targets, with medicinal interest in them likely to increase with the recent clinical approval of inhibitors of the hypoxia-inducible factor prolyl hydroxylases. Human 2OG oxygenases have roles in epigenetics, DNA/RNA damage repair/modification, lipid metabolism, hypoxia sensing, modification of the translational machinery, epidermal growth factor-like protein modification, and in collagen biosynthesis.…”

“…Human 2OG oxygenases have roles in epigenetics, DNA/RNA damage repair/modification, lipid metabolism, hypoxia sensing, modification of the translational machinery, epidermal growth factor-like protein modification, and in collagen biosynthesis. [1][2][3][4] Plant 2OG oxygenases are important agrochemical targets. 2OG oxygenase catalysis typically involves coupling of dioxygen-mediated decarboxylation of 2OG with two-electron substrate oxidation (commonly hydroxylation; Figure 1A).…”

“…All identified 2OG oxygenases use Fe II as a cofactor, though structurally homologous enzymes can bind other metals and catalyse other reaction types. [1][2][3][4] Pioneering work showed that l-ascorbate (l-Asc) enhances the activity of the procollagen prolyl-hydroxylases. [5] The role of l-Asc in enhancing the activity of 2OG-dependent procollagen prolyl hydroxylases is linked to the disease scurvy, which involves impaired collagen biosynthesis, due to lack of l-Asc (and maybe other redox agents).…”

“…The Fe II ‐ and 2‐oxoglutarate (2OG)‐dependent oxygenase superfamily of structurally and mechanistically related enzymes is widely distributed throughout much of biology . Some human 2OG oxygenases are current therapeutic targets, with medicinal interest in them likely to increase with the recent clinical approval of inhibitors of the hypoxia‐inducible factor prolyl hydroxylases.…”

A small-molecule probe for monitoring binding to prolyl hydroxylase domain 2 by fluorescence polarisation

“…Encouraged by this result, we then investigated the biological applications of probe 12. First, a solid phase extraction (SPE)-MS coupled assay 16 was performed to evaluate the potency of probe 12 for PHD2 inhibition. The resultant IC 50 was 166 AE 3 nM, which compares favourably with a PHD inhibitor approved for clinical use to treat anaemia associated with chronic kidney disease (CKD) 17 (FG-4592, IC 50 : 2587 AE 20 nM) (Fig.…”