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

项目总结： 小分子药物JTE-607是20年前发现的，它可以抑制 促炎细胞因子。动物研究表明，JTE-607可用于治疗多发性硬化症 炎症性疾病，包括感染性休克、急性损伤和内毒素血症，它有 通过健康的人体志愿者临床研究取得进展。最近，人们发现 该化合物还具有抗肿瘤活性。对急性骨髓性白血病尤其有效。 白血病(AML)和尤因肉瘤。尽管有这些有希望的药理学研究，但 到目前为止，JTE-607的作用机制尚不清楚。最近发表的两项研究 揭示了JTE-607是一种在细胞内转化为化合物2(Cmp2)的前药，它 特异性地与CPSF73蛋白结合，CPSF73蛋白是一种重要的mRNA3‘末端加工因子。The 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，即内切核试剂。 切割和添加一串腺苷(多聚腺苷)。CPSF73是 负责切割步骤的核酸内切酶。有人提出，JTE-607可以杀死癌症 通过诱导mRNA3‘处理和转录终止缺陷，进而导致 基因组不稳定和细胞死亡。然而，JTE-607还没有在人的mRNA中进行直接测试 目前尚不清楚为什么JTE-607只针对特定的癌症类型。我们的目标是确定 决定药物敏感性的RNA序列和蛋白质“传感器”。这些研究 将揭示一种新型抗炎抗癌的深入作用机制 化合物。对JTE-607抗性mRNA3‘处理的特征可能识别新的 靶点(S)在未来的药物开发中阻断mRNA3‘的加工。从…的角度来看 基础科学，JTE-607为剖析mRNA3‘的机制提供了独特的工具 对mRNA3‘的多种加工模式的加工和发现将对 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.