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

Lennart Brewitz*, Yu Nakashima, Sonia K. Piasecka, Eidarus Salah, Sally C. Fletcher, Anthony Tumber, Thomas P. Corner, Tristan J. Kennedy, Giorgia Fiorini, Armin Thalhammer, Kirsten E. Christensen, Mathew L. Coleman*, Christopher J. Schofield*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

7 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)10849-10865
ページ数17
ジャーナルJournal of Medicinal Chemistry
66
15
DOI
出版ステータス出版済み - 2023/08/10

ASJC Scopus 主題領域

  • 分子医療
  • 創薬

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