Center for Integrative Chemical Biology and Drug Discovery, Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Med Chem. 2011 Sep 8;54(17):6139-50. doi: 10.1021/jm200903z. Epub 2011 Aug 5.
Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.
蛋白赖氨酸甲基转移酶 G9a 通过组蛋白 H3 赖氨酸 9（H3K9me2）的二甲基化以及肿瘤抑制因子 p53 等非组蛋白蛋白的二甲基化，在多种基因的转录抑制中发挥关键作用。我们之前通过基于结构的设计和以 BIX01294（1）为代表的喹唑啉支架的结构活性关系（SAR）探索，发现了 UNC0321（3），这是迄今为止最有效的 G9a 抑制剂。尽管其体外活性非常高，但化合物 3 的细胞活性不足。为了提高细胞膜通透性同时保持高体外活性，设计并合成了几代新的类似物，从而发现了一些新型 G9a 抑制剂，如 UNC0646（6）和 UNC0631（7），它们在多种细胞系中具有优异的活性，并且在功能活性与细胞毒性之间有很好的分离。这些有效 G9a 抑制剂的设计、合成和细胞 SAR 描述如下。
