Synthesis of novel pyridine-carboxylates as small-molecule inhibitors of human aspartate/asparagine-β-hydroxylase

Journal article

The human 2-oxoglutarate (2OG)-dependent oxygenase aspartate/asparagine-β-hydroxylase (AspH) is a potential medicinal chemistry target for anti-cancer therapy. AspH is overexpressed on the cell surface of invasive cancer cells and accepts epidermal growth factor-like domain (EGFDs) substrates with a non-canonical ( 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 using a mass spectrometry based assay employing 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 the development of AspH inhibitors suitable for in vivo use.

Authors: Brewitz, L; Tumber, A; Thalhammer, A; Salah, E; Christensen, KE

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: ChemMedChem
• Volume: 15
• Issue: 2020
• Pages: 1139 –1149
• Publication date: 2020-04-24
• Acceptance date: 2020-04-21
• DOI: 10.1002/cmdc.202000147
• EISSN: 1860-7187
• ISSN: 1860-7179
• Pmid: 32330361
• Language: English
• Keywords: hydroxylase inhibitor; FFR; Aspartate/asparagine-β-hydroxylase / AspH / BAH / HAAH; pyridine-2,4-dicarboxylic acid / 2,4-PDCA; JmjC lysine-specific demethylase / KDM; 2-oxoglutarate / α-ketoglutarate dependent oxygenase