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Synthesis of Novel Pyridine-Carboxylates as Small-Molecule Inhibitors of Human Aspartate/Asparagine-β-Hydroxylase.

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.

SUBMITTER: Brewitz L

PROVIDER: S-EPMC7383925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Aspartate/asparagine-β-hydroxylase: a high-throughput mass spectrometric assay for discovery of small molecule inhibitors.

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