Cytosine-Based TET Enzyme Inhibitors
Cytosine-Based TET Enzyme Inhibitors
复制标题
DOI：
10.1021/acsmedchemlett.8b00474
复制
发表时间：
2019-02-01
影响因子：
4.2
通讯作者：
Kennedy, Andrew J.
中科院分区：
文献类型：
--
作者：
Chua, Gabriella N. L.;Wassarman, Kelly L.;Kennedy, Andrew J.
DNA 甲基化因其在调节局部基因转录中的关键作用而被称为首要表观遗传标记。整个基因组中 DNA 甲基化格局的变化发生在细胞转变过程中，例如分化和神经元可塑性改变，并在癌症等疾病状态下变得失调。已知 TET 酶家族通过识别 S-甲基胞嘧啶并通过 Fe(II)/α-酮戊二酸依赖性机制氧化甲基，负责催化 DNA 去甲基化的逆过程。在这里，我们描述了新型基于胞嘧啶的 TET 酶抑制剂的设计、合成和评估，这是一类以前尚未开发但在表观遗传学领域广泛需要的小分子探针。我们发现了一种有前景的基于胞嘧啶的先导化合物 Bobcat339，它对 TET1 和 TET2 具有中μM 抑制剂活性，但不抑制 DNA 甲基转移酶 DNMT3a。 TET 酶活性位点的计算机模型用于合理化 Bobcat339 和其他基于胞嘧啶的抑制剂的活性。这些新的分子工具将有助于表观遗传学领域，并作为针对 DNA 甲基化和基因转录的新疗法的起点。
DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states such as cancer. The TET family of enzymes is known to be responsible for catalyzing the reverse process that is DNA demethylation by recognizing S-methylcytosine and oxidizing the methyl group via an Fe(II)/alpha-ketoglutarate-dependent mechanism. Here, we describe the design, synthesis, and evaluation of novel cytosine-based TET enzyme inhibitors, a class of small molecule probes previously underdeveloped but broadly desired in the field of epigenetics. We identify a promising cytosine-based lead compound, Bobcat339, that has mid-mu M inhibitor activity against TET1 and TET2, but does not inhibit the DNA methyltransferase, DNMT3a. In silico modeling of the TET enzyme active site is used to rationalize the activity of Bobcat339 and other cytosine-based inhibitors. These new molecular tools will be useful to the field of epigenetics and serve as a starting point for new therapeutics that target DNA methylation and gene transcription.