Development of JS-K as an anti-leukemic agent

描述(申请人提供)：我们先前已经证明一氧化氮(NO)诱导急性髓系白血病(AML)细胞分化和凋亡。谷胱甘肽S转移酶(GST)参与多药耐药，在急性髓细胞白血病分离株中表达上调。我们设计了一类在GST催化下与谷胱甘肽相互作用释放NO的重氮二酸酯前药。通过广泛的先导优化筛选这些化合物的文库，从而确定O2-(2，4-二硝基苯基)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1，2-diolate或JS-K)是这类化合物中最具活性的化合物。JS-K在体内外均表现出较强的抗白血病活性。JS-K具有极具挑战性的溶解性。初步药理研究表明，JS-K与血液成分发生反应。本研究项目的目标是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递送系统，该系统将在体内溶解和稳定JS-K。我们将追求以下目标：1-为JS-K开发胶束配方。利用Pluronics(R)，我们将开发JS-K的胶束配方，旨在增强其增溶作用，降低其与血液成分的反应性。2-研究JS-K胶束制剂的药理性质。使用目标1中开发的胶束配方，我们将研究JS-K在小鼠身上的药理作用。3-研究JS-K胶束制剂对小鼠白血病模型的体内疗效。利用目标1中开发的配方，我们将利用NOD/SCID IL2R？基因缺失小鼠的AML异种移植模型，在体内研究JS-K的抗白血病特性。在这项工作完成后，我们将有一个可行的JS-K配方用于临床开发。这项工作将为我们的武器库增加一类新的有效抗白血病药物。公共卫生相关性：非常需要治疗急性髓系白血病(AML)的新药。该项目所做的工作将开发一种名为JS-K的治疗AML的新药。这项工作将极大地改进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.