Abstract
The human 2‐oxoglutarate (2OG)‐dependent oxygenase aspartate/asparagine‐β‐hydroxylase (AspH) is a potential medicinal chemistry target for anticancer therapy. AspH is present on the cell surface of invasive cancer cells and accepts epidermal growth factor‐like domain (EGFD) substrates with a noncanonical (i. e., Cys 1–2, 3–4, 5–6) disulfide pattern. We report a concise synthesis of C‐3‐substituted derivatives of pyridine‐2,4‐dicarboxylic acid (2,4‐PDCA) as 2OG competitors for use in SAR studies on AspH inhibition. AspH inhibition was assayed by using a mass spectrometry‐based assay with a stable thioether analogue of a natural EGFD AspH substrate. Certain C‐3‐substituted 2,4‐PDCA derivatives were potent AspH inhibitors, manifesting selectivity over some, but not all, other tested human 2OG oxygenases. The results raise questions about the use of pyridine‐carboxylate‐related 2OG analogues as selective functional probes for specific 2OG oxygenases, and should aid in the development of AspH inhibitors suitable for in vivo use.
Highlights
Introduction butyrobetaine dioxygenase (BBOX),[13] most 2OG oxygenase inhibitors are active-site FeII ligands/2OG competitors.[10]
The human 2OG oxygenase aspartate/asparagine-β-hydroxylase (AspH, BAH, HAAH) catalyses the hydroxylation of conserved Asp and Asn residues in epidermal growth factor-like domains (EGFDs),[15] which include the extracellular domains of the notch receptor and its ligands.[16]
AspH inhibitors in cell-based experiments[25] and l-ascorbate based AspH inhibitors have been used in cellular and animal experiments.[22a,26] Studies focusing on the development of nitrogen-containing heteroaromatic scaffolds for AspH inhibition have not been reported despite the prominence of these scaffolds in approved active pharmaceutical ingredients (APIs), including anticancer drugs and 2OG oxygenase inhibitors.[27]
Summary
Introduction butyrobetaine dioxygenase (BBOX),[13] most 2OG oxygenase inhibitors are active-site FeII ligands/2OG competitors.[10]. AspH is reported to be translocalised from the endoplasmic reticulum (ER) to the cell surface membrane resulting in enhanced tumour invasiveness and a diminished patient survival rate.[17b,19] AspH is strongly hypoxically regulated[20] and may have a role in hypoxia sensing.[21] AspH is an interesting potential target from a cancer medicinal chemistry perspective.[22]. AspH inhibitors in cell-based experiments[25] and l-ascorbate based AspH inhibitors have been used in cellular and animal experiments.[22a,26] Studies focusing on the development of nitrogen-containing heteroaromatic scaffolds for AspH inhibition have not been reported despite the prominence of these scaffolds in approved active pharmaceutical ingredients (APIs), including anticancer drugs and 2OG oxygenase inhibitors.[27]. The discrepancy between the potential of a AspH as a medicinal chemistry target and the limited effort of developing efficient small-molecule AspH inhibitors for clinical use likely relates to the lack of efficient assays for isolated AspH. These reveal that AspH accepts EGFDs with
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