Center for Integrative Chemical Biology and Drug Discovery, Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Med Chem. 2010 Aug 12;53(15):5844-57. doi: 10.1021/jm100478y.
Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation 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 cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
蛋白赖氨酸甲基转移酶 G9a 可催化组蛋白 H3 赖氨酸 9（H3K9）和 p53 赖氨酸 373（K373）的甲基化，在人类癌症中过度表达。G9a 的基因敲低抑制癌细胞生长，而 p53 K373 的二甲基化导致 p53 失活。以 G9a 和 GLP 的选择性小分子抑制剂 3a（BIX01294）为代表的 2,4-二氨基-6,7-二甲氧基喹唑啉模板的初始 SAR 探索导致发现了 10（UNC0224）作为一种有效的 G9a 抑制剂，具有优异的选择性。获得了 G9a-10 复合物的高分辨率 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见解，对 10 的 7-二甲基氨基丙氧基侧链进行优化，发现了 29（UNC0321）（Morrison K(i) = 63 pM），这是第一个具有皮摩尔效力的 G9a 抑制剂，也是迄今为止最有效的 G9a 抑制剂。
