Development of JS-K as an anti-leukemic agent

摘要 我们先前已经表明，一氧化氮（NO）诱导分化和凋亡， 急性髓性白血病（AML）细胞。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。我们设计了一类 二醇二氮烯鎓前药在与谷胱甘肽相互作用时释放NO， GST催化的反应。筛选这些化合物的库与广泛的铅 优化导致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作为活性最高的 这类化合物。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。初步的药理学研究 显示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，我们将努力 开发一种纳米级的输送系统，将溶解和稳定JS-K在体内。 我们将努力实现以下目标： 1-JS-K胶束制剂的开发。使用Pluronics，我们将开发一种 JS-K的胶束制剂旨在增强其增溶作用并降低其 与血液成分反应。 2-研究JS-K在胶束制剂中的药理学性质。胶束 在目标1中开发的制剂中，我们将在小鼠中研究JS-K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 在NOD/SCID IL 2 R中使用AML异种移植模型的体内JS-K？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 发展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。叙事 与公共卫生的相关性：非常需要治疗急性骨髓性白血病的新药 白血病（AML）。在这个项目中所做的工作将开发一种名为JS-K的新药， AML的治疗。这项工作将大大改善AML的治疗， 其他癌症。

Abstract 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¿, 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. Narrative Relevance to public health: 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.