Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors
Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors
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DOI：
10.1021/acs.jmedchem.6b01303
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发表时间：
2016-12-22
影响因子：
7.3
通讯作者：
Ferguson, Andrew D.
中科院分区：
文献类型：
--
作者：
Cowen, Scott D.;Russell, Daniel;Ferguson, Andrew D.
蛋白质赖氨酸甲基转移酶 (KMT) 已成为表观遗传信号传导的重要调节因子。这些酶催化供体甲基从辅因子 S-腺苷甲硫氨酸转移到组蛋白上的特定受体赖氨酸残基，从而导致染色质结构和转录调控的变化。这些酶还会甲基化一系列非组蛋白，这表明它们影响细胞生理学的其他机制。据报道，SMYD2 是一种致癌甲基转移酶，可抑制肿瘤抑制蛋白 p53 和 RB 的功能活性。 HTS 筛选鉴定出五种不同的底物竞争性化学品系列。 SMYD2 配体晶体结构的确定对“命中先导”设计工作做出了重大贡献，最终创建了有效的选择性抑制剂，用于了解 SMYD2 抑制的功能后果。总而言之，这些结果对针对 KMT 的抑制剂设计具有广泛的影响，并清楚地证明了开发针对这些酶的新疗法的潜力。
Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical,series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.