Development of JS-K as an anti-leukemic agent

摘要 我们先前已经证明，一氧化氮(NO)可以诱导细胞分化和细胞凋亡。 急性髓系白血病(AML)细胞。谷胱甘肽S转移酶(GST)参与了 多药耐药，在急性髓系白血病分离株中上调。我们设计了一个班级 与谷胱甘肽相互作用释放NO的二氮尿苷前药 反应由GST催化。筛选具有广泛铅含量的化合物文库 优化得到了O2-(2，4-二硝基苯基)1-[(4- Ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1，2-diolate或JS-K是最活跃的 这一类的化合物。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。初步的药理研究已经 结果表明，JS-K与血液成分发生反应。这项研究项目的目标是 JS-K用于治疗AML的临床前开发。为此，我们将努力 开发一种在体内增溶和稳定JS-K的纳米级给药系统。 我们将致力于实现以下目标： 1-为JS-K开发胶束配方。使用Pluronics？，我们将开发一种 JS-K增溶降粘胶束配方 与血液成分的反应性。 2-研究JS-K胶束制剂的药理性质。使用胶束 目标1中开发的配方，我们将在小鼠身上研究JS-K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。 使用在目标1中开发的配方，我们将研究其抗白血病特性 JS-K在NOD/SCID IL2R？基因缺失小鼠AML异种移植模型中的应用 在这项工作完成后，我们将有一个可用于临床的JS-K配方 发展。这项工作将为我们的武器库增添一批新的强大的反 白血病药物。叙述性 与公众健康相关：非常需要治疗急性髓系白血病的新药 白血病(AML)。该项目所做的工作将开发一种名为JS-K的新药 急性髓系白血病的治疗。这项工作将极大地改善急性髓系白血病和 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.