Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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DOI：
10.1021/jm100478y
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发表时间：
2010-08-12
影响因子：
7.3
通讯作者：
Jin J
中科院分区：
文献类型：
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作者：
Liu F;Chen X;Allali-Hassani A;Quinn AM;Wigle TJ;Wasney GA;Dong A;Senisterra G;Chau I;Siarheyeva A;Norris JL;Kireev DB;Jadhav A;Herold JM;Janzen WP;Arrowsmith CH;Frye SV;Brown PJ;Simeonov A;Vedadi M;Jin J
蛋白赖氨酸甲基转移酶G9a在人类癌症中过度表达，它催化组蛋白H3赖氨酸9 （H3K9）和p53赖氨酸373 （K373）的甲基化。基因敲低G9a抑制癌细胞生长，p53 K373的二甲基化导致p53失活。对以3a （BIX01294）为代表的2,4-二氨基-6,7-二甲氧基喹唑啉模板进行初步SAR探索，发现10 （UNC0224）是G9a和GLP的选择性小分子抑制剂，具有良好的选择性。获得了G9a-10配合物的高分辨率x射线晶体结构，这是G9a与小分子抑制剂的第一个共晶结构。基于该共晶结构揭示的结构信息，对7-二甲氨基丙氧基侧链10进行优化，发现了29 (UNC0321) (Morrison Ki = 63 pM)，这是迄今为止第一个具有皮摩尔效价的G9a抑制剂，也是迄今为止最有效的G9a抑制剂。
Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is over expressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth and the di-methylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. Based on the structural insights revealed by this co-crystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
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