Fluorinated derivatives of pyridine-2,4-dicarboxylate are potent inhibitors of human 2-oxoglutarate dependent oxygenases

Journal article

2-Oxoglutarate (2OG) oxygenases have important roles in human biology and are validated medicinal chemistry targets. Improving the selectivity profile of broad-spectrum 2OG oxygenase inhibitors may help enable the identification of selective inhibitors for use in functional assignment work. We report the synthesis of F- and CF3-substituted derivatives of the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylate (2,4-PDCA). Their inhibition selectivity profile against selected functionally distinct human 2OG oxygenases was determined using mass spectrometry-based assays. F-substituted 2,4-PDCA derivatives efficiently inhibit the 2OG oxygenases aspartate/asparagine-β-hydroxylase (AspH) and the JmjC lysine-specific Nε-demethylase 4E (KDM4E); The F- and CF3-substituted 2,4-PDCA derivatives were all less efficient inhibitors of the tested 2OG oxygenases than 2,4-PDCA itself, except for the C5 F-substituted 2,4-PDCA derivative which inhibited AspH with a similar efficiency as 2,4-PDCA. Notably, the introduction of a F- or CF3-substituent at the C5 position of 2,4-PDCA results in a substantial increase in selectivity for AspH over KDM4E compared to 2,4-PDCA. Crystallographic studies inform on the structural basis of our observations, which exemplifies how a small change on a 2OG analogue can make a substantial difference in the potency of 2OG oxygenase inhibition.

Authors: Brewitz, L; Nakashima, Y; Tumber, A; Salah, E; Schofield, CJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Fluorine Chemistry
• Volume: 247
• Article number: 109804
• Publication date: 2021-05-13
• Acceptance date: 2021-05-01
• DOI: 10.1016/j.jfluchem.2021.109804
• ISSN: 0022-1139
• Language: English
• Keywords: aspartate/asparagine-β-hydroxylase / AspH / BAH / HAAH; 2-oxoglutarate / α-ketoglutarate dependent oxygenase; JmjC lysine demethylase / KDM; pyridine-2,4-dicarboxylic acid / 2,4-PDCA; FFR; ribosomal oxygenase 2 / RIOX2 / Mina53; fluorinated hydroxylase inhibitor