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

Abstract

Highlights Synthesis of fluorinated pyridine-2,4-dicarboxylic acid (2,4-PDCA) derivatives Fluorinated 2,4-PDCA derivatives inhibit 2-oxoglutarate dependent oxygenases 2,4-PDCA C5 substituents increase the selectivity for AspH over KDM4 inhibition

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

“…Further, considering the pleiotropic effects that NOG and its derivatives exhibit in cellular studies, application of related 2-oxo acid derivatives to cells may trigger phenotypes useful in identifying previously overlooked 2OG oxygenase/2OG-utilizing enzyme functions. FIH 76 and AspH 22 – 26 are proposed medicinal chemistry targets and the use of (partially) selective 2OG derivatives, such as 13 or corresponding esters in cellular studies may help to improve the currently limited understanding on their biochemical roles and complement similar approaches using heterocyclic small-molecules 24 , 76 – 81 .…”

5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5

“…Interestingly, the results reveal that 5-fluoro-2,4-PDCA ( 15 ) is approximately fivefold more efficient in inhibiting JMJD5 than the isomeric 3-fluoro-2,4-PDCA ( 13 ), but is approximately ninefold less efficient than 2,4-PDCA ( 1 ) (IC 50 ∼ 4.5 μM; Table , entry xv). Also, note that 15 is reported to inhibit AspH with similar efficiency to 1 ; thus, 15 is ∼90-fold more selective in inhibiting AspH than JMJD5 compared to 1 , which is only ∼15-fold more selective in inhibiting AspH than JMJD5. By contrast with the observed inhibition of JMJD5 by isomeric 13 and 15 , the corresponding C3 and C5 trifluoromethyl-substituted 2,4-PDCA derivatives 14 and 16 did not inhibit JMJD5 (IC 50 > 50 μM; Table ), implying that a fluorine substituent at the C3 or C5 position is preferred for JMJD5 inhibition over a sterically bulkier trifluoromethyl substituent.…”

“…Human JMJD5 is inhibited by 2,4-PDCA ( 1 ), which is a 2OG mimic and which is a relatively broad-spectrum 2OG oxygenase inhibitor. ,, However, the potency with which 1 inhibits 2OG oxygenases varies substantially . Hence, we envisaged that derivatives of 1 may be developed to obtain improved JMJD5-selective inhibitors.…”

Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation

“…Indeed, HIF-α prolyl hydroxylase inhibitors are used for the treatment of anemia ( 121 ). By informing on the cellular substrates of AspH, we hope that the results presented here will help enable the development of potent and selective small-molecule inhibitors of AspH, which is of interest from a cancer treatment perspective ( 54 , 55 , 122 , 123 , 124 , 125 , 126 , 127 ).…”