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

Figure 1
<div class='caption-title'>Synthesis of 5-Aminoalkyl-substituted2,4-PDCA Derivatives</div>
Figure 2
Brewitz L, Nakashima Y, Piasecka SK, Salah E, Fletcher SC, Tumber A, Corner TP, Kennedy TJ, Fiorini G, Thalhammer A, Christensen KE, Coleman ML, Schofield CJ
OpenAccess logo J Med Chem 66 10849-10865 (2023)
Related entries: 7dyu, 7dyv, 7dyw, 7dyx

Cited: 2 times
EuropePMC logo PMID: 37527664

Abstract

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 has been reported to have activity as a histone protease, as an Nε-methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5.

Articles - 7dyt mentioned but not cited (1)

  1. 5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5. Brewitz L, Nakashima Y, Piasecka SK, Salah E, Fletcher SC, Tumber A, Corner TP, Kennedy TJ, Fiorini G, Thalhammer A, Christensen KE, Coleman ML, Schofield CJ. J Med Chem 66 10849-10865 (2023)


Articles citing this publication (1)

  1. Structure-guided optimisation of N-hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-α. Corner TP, Teo RZR, Wu Y, Salah E, Nakashima Y, Fiorini G, Tumber A, Brasnett A, Holt-Martyn JP, Figg WD, Zhang X, Brewitz L, Schofield CJ. Chem Sci 14 12098-12120 (2023)


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