Molecular basis of the anti-cancer and anti-inflammation activities of JTE607

项目概要： 小分子药物JTE-607是20年前发现的，可以抑制 促炎细胞因子。动物研究表明，JTE-607可用于治疗多种 炎症性疾病，包括败血性休克、急性损伤和内毒素血症，并且它具有 通过健康人类志愿者临床研究取得进展。最近人们发现， 该化合物还显示出抗肿瘤活性。它对急性髓系白血病特别有效 白血病（AML）和尤文氏肉瘤。尽管这些有希望的药理学研究， 直到最近，JTE-607的作用机制仍然未知。最近发表的两项研究 揭示了JTE-607是在细胞中转化为化合物2（Cmp 2）的前药， 特异性结合CPSF 73蛋白，一种必需的mRNA 3'末端加工因子。的3' 几乎所有真核生物mRNA的末端都是在两个催化步骤中形成的， 切割和添加一串腺苷（聚腺苷酸化）。CPSF 73是 核酸内切酶负责切割步骤。有人提出JTE-607可以杀死癌症 细胞通过诱导mRNA 3'加工和转录终止缺陷，这反过来又导致 基因组不稳定和细胞死亡。然而，JTE-607尚未在人mRNA中直接测试 目前还不清楚为什么JTE-607只针对特定的癌症类型。我们的目标是找出 RNA序列和决定药物敏感性的蛋白质“传感器”。这些研究 将揭示一种新型抗炎抗癌药物的深入作用机制， 化合物. JTE-607抗性mRNA 3'加工的表征可以鉴定新的 在未来的药物开发中阻断mRNA 3'加工的靶点。视角下 JTE-607为剖析mRNA 3'端的机制提供了一个独特的工具， mRNA 3'加工的多种模式的发现将对 我们对真核基因表达的基本理解。

Project Summary: The small molecule drug JTE-607 was discovered 20 years ago that inhibits the production of pro-inflammatory cytokines. Animal studies showed that JTE-607 can be used to treat multiple inflammation diseases, including septic shock, acute injury, and endotoxemia, and it has progressed through healthy human volunteer clinical studies. More recently it was discovered that this compound also displays anti-tumor activities. It is particularly potent against acute myeloid leukemia (AML) and Ewing’s sarcoma. Despite these promising pharmacological studies, the mechanism of action of JTE-607 remained unknown until recently. Two studies published recently revealed that JTE-607 is a prodrug that is converted to Compound 2 (Cmp2) in cells, which specifically binds to the CPSF73 protein, an essential mRNA 3’ end processing factor. The 3’ ends of almost all eukaryotic mRNAs are formed in two catalytic steps, an endonucleolytic cleavage and the addition of a string of adenosines (polyadenylation). CPSF73 is the endonuclease responsible for the cleavage step. It has been proposed that JTE-607 kills cancer cells by inducing mRNA 3’ processing and transcription termination defects, which, in turn, cause genome instability and cell death. However, JTE-607 has not been directly tested in human mRNA 3’ processing and it is unclear why JTE-607 only targets specific cancer types. We aim to identify the RNA sequences and the protein “sensors” that determine the drug sensitivity.These studies will reveal the in-depth mechanism of action of a novel anti-inflammation and anti-cancer compound. Characterization of the JTE-607-resistant mRNA 3’ processing may identify novel target(s) for blocking mRNA 3’ processing in future drug development. From the perspective of basic science, JTE-607 provides a unique tool for dissecting the mechanism of mRNA 3’ processing and the discovery of multiple modes of mRNA 3’ processing will have implications for our fundamental understanding of eukaryotic gene expression.