Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases.
Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases.
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DOI：
10.1016/j.jmb.2010.04.048
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发表时间：
2010-07-02
影响因子：
5.6
通讯作者：
Cheng X
中科院分区：
文献类型：
--
作者：
Chang Y;Ganesh T;Horton JR;Spannhoff A;Liu J;Sun A;Zhang X;Bedford MT;Shinkai Y;Snyder JP;Cheng X
动态组蛋白赖氨酸甲基化涉及修饰酶（写入器）、去除修饰的酶（擦除器）和组蛋白密码的读取器的活动。这些活性的一个共同特征是识别甲基化和未甲基化状态的赖氨酸，无论它们是底物、反应产物还是结合伴侣。我们应用了这样的概念，即通过包括5-氨基戊氧基部分，将赖氨酸模拟物添加到组蛋白H3赖氨酸9甲基转移酶G9 a和G9 a样蛋白（GLP）的已建立抑制剂（BIX-01294）中，该5-氨基戊氧基部分插入靶赖氨酸结合通道并被GLP甲基化，尽管缓慢。该化合物在体外增强了其效力，并在体内降低了细胞毒性。我们建议在设计其他甲基赖氨酸书写器、擦除器和阅读器的小分子抑制剂时，应考虑加入赖氨酸或甲基赖氨酸模拟物。
Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers) and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein (GLP) by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by GLP, albeit slowly. The compound enhanced its potency in vitro and reduced cell toxicity in vivo. We suggest that adding a lysine or methyllysine mimic should be considered in the design of small molecule inhibitors for other methyl-lysine writers, erasers and readers.
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影响因子：
16
作者：
Kubicek, Stefan;O'Sullivan, Roderick J.;Jenuwein, Thomas
通讯作者：
Jenuwein, Thomas
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL
影响因子：
3.6
作者：
Hu, WP;Wang, JJ;Hsu, MH
通讯作者：
Hsu, MH
影响因子：
7.3
作者：
Liu F;Chen X;Allali-Hassani A;Quinn AM;Wasney GA;Dong A;Barsyte D;Kozieradzki I;Senisterra G;Chau I;Siarheyeva A;Kireev DB;Jadhav A;Herold JM;Frye SV;Arrowsmith CH;Brown PJ;Simeonov A;Vedadi M;Jin J
通讯作者：
Jin J
DOI：
10.1074/jbc.m807818200
发表时间：
2009-03-27
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Trojer P;Zhang J;Yonezawa M;Schmidt A;Zheng H;Jenuwein T;Reinberg D
通讯作者：
Reinberg D