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

Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate(2OG)-dependent oxygenase that plays important roles in development,circadian rhythm, and cancer through unclear mechanisms. JMJD5 hasbeen reported to have activity as a histone protease, as an N (& epsilon;)-methyl lysine demethylase, and as anarginine residue hydroxylase. Small-molecule JMJD5-selective inhibitorswill be useful for investigating its (patho)physiological roles. Followingthe observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylicacid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitorsmanifesting selectivity for JMJD5 over other human 2OG oxygenases.Crystallographic analyses with five inhibitors imply induced fit bindingand reveal that the 2,4-PDCA C5 substituent orients into the JMJD5substrate-binding pocket. Cellular studies indicate that the leadcompounds display similar phenotypes as reported for clinically observedJMJD5 variants, which have a reduced catalytic activity compared towild-type JMJD5.

Automated summary

Jumonji-C domain-containing protein 5 (JMJD5) is an important 2-oxoglutarate-dependent oxygenase that has various functions in development, circadian rhythm, and cancer. This study discovered potent JMJD5 inhibitors, which are 5-aminoalkyl-substituted derivatives of the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA). Crystallographic analyses showed that these inhibitors bind to JMJD5 in an induced fit manner, with the C5 substituent of 2,4-PDCA binding to the substrate-binding pocket of JMJD5. Cellular studies revealed that these lead compounds displayed similar phenotypes as clinically observed JMJD5 variants with reduced catalytic activity.