Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, U.K.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, B15 2TT Birmingham, U.K.
J Med Chem. 2023 Aug 10;66(15):10849-10865. doi: 10.1021/acs.jmedchem.3c01114. Epub 2023 Aug 1.
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 -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.
Jumonji-C 结构域包含蛋白 5（JMJD5）是一种依赖 2-氧戊二酸（2OG）的加氧酶，通过不明机制在发育、昼夜节律和癌症中发挥重要作用。已经报道 JMJD5 具有组蛋白蛋白酶、α-甲基赖氨酸去甲基酶和精氨酸残基羟化酶的活性。小分子 JMJD5 选择性抑制剂将有助于研究其（病理）生理作用。在观察到广谱 2OG 加氧酶抑制剂吡啶-2,4-二甲酸（2,4-PDCA）是 2OG 竞争性 JMJD5 抑制剂后，我们报告说，5-氨基烷基取代的 2,4-PDCA 衍生物是强效的 JMJD5 抑制剂，对 JMJD5 表现出选择性，而对其他人类 2OG 加氧酶则没有选择性。与五种抑制剂的晶体结构分析表明诱导契合结合，并揭示了 2,4-PDCA C5 取代基朝向 JMJD5 底物结合口袋取向。细胞研究表明，先导化合物表现出与临床观察到的 JMJD5 变体相似的表型，与野生型 JMJD5 相比，其催化活性降低。
