Development of JS-K as an anti-leukemic agent

描述（由申请人提供）：我们以前已经表明，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）参与多药耐药性，并在AML分离株中上调。我们已经设计了一类diazeniumdiolate前药，在GST催化的反应中与谷胱甘肽相互作用后释放NO。用广泛的先导优化筛选这些化合物的库，鉴定出O2-（2，4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]二氮烯-1-鎓-1，2-二醇盐或JS-K为该类中最具活性的化合物。JS-K在体外和体内均显示出有效的抗白血病活性。JS-K具有具有挑战性的溶解度特性。初步药理学研究表明，JS-K与血液成分反应。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-开发JS-K的胶束制剂。使用Pluronics（r），我们将开发JS-K的胶束制剂，旨在增强其溶解性并降低其与血液成分的反应性。2-研究JS-K在胶束制剂中的药理学性质。使用目标1中开发的胶束制剂，我们将研究JS-K在小鼠中的药理学。3-研究JS-K的胶束制剂在小鼠白血病模型中的体内功效。使用目标1中开发的制剂，我们将研究JS-K在体内使用AML异种移植模型在NOD/SCID IL2R？无效小鼠。在这项工作完成后，我们将有一个可行的配方JS-K的临床开发。这项工作将为我们的医疗设备增加一类新的有效的抗白血病药物。公共卫生相关性：对治疗急性髓系白血病（AML）的新药有很大的需求。该项目的工作将开发一种名为JS-K的新药，用于治疗AML。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.