Development of JS-K as an anti-leukemic agent

JS-K作为抗白血病药物的开发

• 批准号: 8205033
• 负责人: Paul J Shami
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205033
• 关键词: Acute Myelocytic Leukemia; Antihypertensive Agents; Apoptosis; Applications Grants; Blood; Blood Vessels; Cells; Clinical; Collaborations; Development; Drug Delivery Systems; Drug Design; Drug Formulations; Family; Glutathione; Glutathione S-Transferase; Goals; Growth; Half-Life; IL2RA gene; Immunologics; Knockout Mice; Lead; Libraries; Malignant Neoplasms; Micelles; Modeling; Multi-Drug Resistance; Mus; National Cancer Institute; Neurologic; Nitric Oxide; Normal Cell; Pharmaceutical Preparations; Pharmacology; Prodrugs; Property; Proteins; Public Health; Reaction; Research Project Grants; Screening procedure; Solubility; Sulfhydryl Compounds; System; Translational Research; Treatment Efficacy; Up-Regulation; Work; Xenograft Model; abstracting; aqueous; cancer cell; cancer therapy; clinical application; design; diazeniumdiolate; dinitrophenyl; improved; in vitro activity; in vivo; leukemia; nanoscale; pre-clinical

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.

摘要 我们之前已经证明一氧化氮（NO）可以诱导细胞分化和凋亡。 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 优化后鉴定出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。

项目成果

Cellular distribution studies of the nitric oxide-generating antineoplastic prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate formulated in Pluronic P123 micelles.

• DOI: 10.1111/jphp.12100
• 发表时间: 2013-09
• 期刊: The Journal of pharmacy and pharmacology
• 作者: Kaur I;Terrazas M;Kosak KM;Kern SE;Boucher KM;Shami PJ
• 通讯作者: Shami PJ

Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs.

• DOI: 10.1021/jm2004128
• 发表时间: 2011-11-24
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Maciag, Anna E.;Nandurdikar, Rahul S.;Hong, Sam Y.;Chakrapan, Harinath;Diwan, Bhalchandra;Morris, Nicole L.;Shami, Paul J.;Shiao, Yih-Horng;Anderson, Lucy M.;Keefer, Larry K.;Saavedra, Joseph E.
• 通讯作者: Saavedra, Joseph E.

Effect of a Pluronic(®) P123 formulation on the nitric oxide-generating drug JS-K.

• DOI: 10.1007/s11095-014-1542-9
• 发表时间: 2015-04
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Kaur, Imit;Kosak, Ken M.;Terrazas, Moises;Herron, James N.;Kern, Steven E.;Boucher, Kenneth M.;Shami, Paul J.
• 通讯作者: Shami, Paul J.

Targeting Glutathione S-transferase M4 in Ewing sarcoma.

• DOI: 10.3389/fped.2014.00083
• 发表时间: 2014
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Zhuo R;Kosak KM;Sankar S;Wiles ET;Sun Y;Zhang J;Ayello J;Prestwich GD;Shami PJ;Cairo MS;Lessnick SL;Luo W
• 通讯作者: Luo W