Development of JS-K as an anti-leukemic agent

描述（由申请人提供）：我们之前已经证明一氧化氮（NO）诱导急性髓性白血病（AML）细胞的分化和凋亡。谷胱甘肽s -转移酶（GST）参与多药耐药，并在AML分离株中上调。我们设计了一类在GST催化下与谷胱甘肽相互作用释放NO的重氮二酸前药。通过广泛的先导优化筛选这些化合物的文库，鉴定出O2-（2,4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]重氮-1-ium-1,2-二甲酸酯或JS-K是这类化合物中最活跃的化合物。JS-K在体外和体内均显示出较强的抗白血病活性。JS-K具有挑战性的溶解度。初步的药理学研究表明，JS-K与血液成分发生反应。该研究项目的目标是JS-K治疗AML的临床前开发。为此，我们将致力于开发一种纳米级的输送系统，可以在体内溶解和稳定JS-K。我们将追求以下目标：1-开发JS-K的胶束配方。利用Pluronics(r)，我们将开发一种JS-K的胶束配方，旨在增强其溶解性并降低其与血液成分的反应性。研究了胶束制剂中JS-K的药理学特性。使用在Aim 1中开发的胶束制剂，我们将在小鼠中研究JS-K的药理学。研究一种胶束制剂JS-K对小鼠白血病模型的体内疗效。使用Aim 1开发的配方，我们将使用NOD/SCID IL2R? AML异种移植模型在体内研究JS-K的抗白血病特性。零的老鼠。这项工作完成后，我们将有一个可用于临床开发的JS-K的可行配方。这项工作将为我们的医疗设备增加一类新的强效抗白血病药物。公共卫生相关性：迫切需要治疗急性髓性白血病（AML）的新药。在这个项目中所做的工作将开发一种名为JS-K的治疗AML的新药。这项工作将大大改善AML和其他癌症的治疗。

DESCRIPTION (provided by applicant): We have previously shown that nitric oxide (NO) induces differentiation and apoptosis in acute myeloid leukemia (AML) cells. Glutathione S-transferases (GST) are involved in multi-drug resistance and are upregulated in AML isolates. We have designed a class of diazeniumdiolate prodrugs that release NO upon interaction with glutathione in a reaction catalyzed by GST. Screening a library of these compounds with extensive lead optimization has led to the identification of O2-(2,4-Dinitrophenyl) 1-[(4- ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K as the most active compound of this class. JS-K has shown potent anti-leukemic activity in vitro and in vivo. JS-K has challenging solubility properties. Preliminary pharmacologic studies have shown that JS-K reacts with blood components. The goal of this research project is the pre-clinical development of JS-K for the treatment of AML. For that purpose we will work on developing a nanoscale delivery system that will solubilize and stabilize JS-K in vivo. We will pursue the following aims: 1- Development of a micellar formulation for JS-K. Using Pluronics(r), we will develop a micellar formulation of JS-K aiming at enhancing its solubilization and decreasing its reactivity with blood components. 2- Study the pharmacologic properties of JS-K in a micellar formulation. Using micellar formulations developed in Aim 1, we will study the pharmacology of JS-K in mice. 3- Study the in vivo efficacy of a micellar formulation of JS-K in mouse leukemia models. Using the formulations developed in Aim 1, we will study the anti-leukemic properties of JS-K in vivo using AML xenograft models in NOD/SCID IL2R?null mice. At the completion of this work, we will have a workable formulation of JS-K for clinical development. This work will add to our armamentarium a new class of potent anti- leukemic agents. PUBLIC HEALTH RELEVANCE: There is a great need for new drugs to treat Acute Myeloid Leukemia (AML). Work done in this project will develop a new drug called JS-K for the treatment of AML. This work will lead to great improvements in treatment of AML and other cancers.