5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.
5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.
复制标题
DOI：
10.1021/acs.jmedchem.3c01114
复制
发表时间：
2023-08-10
影响因子：
7.3
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Brewitz, Lennart;Nakashima, Yu;Piasecka, Sonia K.;Salah, Eidarus;Fletcher, Sally C.;Tumber, Anthony;Corner, Thomas P.;Kennedy, Tristan J.;Fiorini, Giorgia;Thalhammer, Armin;Christensen, Kirsten E.;Coleman, Mathew L.;Schofield, Christopher J.
含Jumonji-C结构域蛋白5（JMJD 5）是2-酮戊二酸（2 OG）依赖性加氧酶，其通过不清楚的机制在发育、昼夜节律和癌症中起重要作用。据报道，JMJD 5具有作为组蛋白蛋白酶、作为Nε-甲基赖氨酸脱甲基酶和作为精氨酸残基羟化酶的活性。小分子JMJD 5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2 OG加氧酶抑制剂吡啶-2，4-二羧酸（2，4-PDCA）是2 OG竞争性JMJD 5抑制剂之后，我们报告了5-氨基烷基取代的2，4-PDCA衍生物是有效的JMJD 5抑制剂，其表现出对JMJD 5的选择性超过其他人2 OG加氧酶。用五种抑制剂的晶体学分析暗示诱导的拟合结合，并揭示2，4-PDCA C5取代基定向到JMJD 5底物结合口袋中。细胞研究表明，先导化合物显示出与临床观察到的JMJD 5变体相似的表型，与野生型JMJD 5相比，JMJD 5变体具有降低的催化活性。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Islam, Md Saiful;Markoulides, Marios;Chowdhury, Rasheduzzaman;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.
影响因子：
3.4
作者：
Beck H;Jeske M;Thede K;Stoll F;Flamme I;Akbaba M;Ergüden JK;Karig G;Keldenich J;Oehme F;Militzer HC;Hartung IV;Thuss U
通讯作者：
Thuss U
影响因子：
4.5
作者：
Amendola PG;Zaghet N;Ramalho JJ;Vilstrup Johansen J;Boxem M;Salcini AE
通讯作者：
Salcini AE
影响因子：
3.4
作者：
Holt-Martyn, James P.;Chowdhury, Rasheduzzaman;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH