Development of JS-K as an anti-leukemic agent
JS-K作为抗白血病药物的开发
基本信息
- 批准号:8025951
- 负责人:
- 金额:$ 30.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Acute Myelocytic LeukemiaAntihypertensive AgentsApoptosisApplications GrantsBloodBlood VesselsCellsClinicalCollaborationsDevelopmentDrug Delivery SystemsDrug DesignDrug FormulationsFamilyGlutathioneGlutathione S-TransferaseGoalsGrowthHalf-LifeHealthIL2RA geneImmunologicsKnockout MiceLeadLibrariesMalignant NeoplasmsMicellesModelingMulti-Drug ResistanceMusNational Cancer InstituteNeurologicNitric OxideNormal CellPharmaceutical PreparationsPharmacologyPluronicsProdrugsPropertyProteinsReactionResearch Project GrantsScreening procedureSolubilitySulfhydryl CompoundsSystemTranslational ResearchTreatment EfficacyUp-RegulationWorkXenograft Modelaqueouscancer cellcancer therapyclinical applicationdesigndiazeniumdiolatedinitrophenylimprovedin vitro activityin vivoleukemiananoscalepre-clinical
项目摘要
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul J Shami其他文献
Novel Data Analytics Identify Predictors of Quality-of-Life Trajectories in Patients with AML or High-Risk Myeloid Neoplasms
新颖的数据分析确定急性髓系白血病或高危髓系肿瘤患者生活质量轨迹的预测因子
- DOI:
10.1182/blood-2022-165437 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:23.100
- 作者:
Jordan Gauthier;Bianca Furtuna;Jacopo Mangiavacchi;Shahrzad Gholami;Juan Lavista Ferres;Rahul Dodhia;Amir T. Fathi;Andrew M. Brunner;Aaron T. Gerds;Mikkael A. Sekeres;Bruno C. Medeiros;Eunice S. Wang;Paul J Shami;Kehinde Adekola;Selina M. Luger;Maria R. Baer;David A Rizzieri;Tanya Wildes;Jamie L. Koprivnikar;Julie Smith;Mohamed L. Sorror - 通讯作者:
Mohamed L. Sorror
Development of a Comprehensive Program for Evaluation of Hereditary Predisposition to Hematologic Malignancies
- DOI:
10.1182/blood-2022-170000 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Jennie Vagher;Bryan D. Huber;Luke Maese;Archana M Agarwal;Afaf Osman;Ami B. Patel;Tsewang Tashi;Paul J Shami;Tibor Kovacsovics;Julie D. Asch;Charles J. Parker;Srinivas K. Tantravahi - 通讯作者:
Srinivas K. Tantravahi
Revumenib Monotherapy in Patients with Relapsed/Refractory emKMT2Ar/em Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study
Revumenib 单药治疗复发/难治性 emKMT2Ar/em 急性白血病患者:Augment-101 期 1/2 研究的疗效和安全性结果
- DOI:
10.1182/blood-2023-189762 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:23.100
- 作者:
Ibrahim Aldoss;Ghayas C. Issa;Michael J Thirman;John DiPersio;Martha Arellano;James S. Blachly;Gabriel Mannis;Alexander Perl;David Dickens;Christine M. McMahon;Elie Traer;C. Michel Zwaan;Carolyn Grove;Richard Stone;Paul J Shami;Ioannis Mantzaris;Matthew Greenwood;Neerav Shukla;Branko Cuglievan;Yu Gu;Eytan M. Stein - 通讯作者:
Eytan M. Stein
Revumenib Monotherapy in Patients with Relapsed/Refractory <em>KMT2Ar</em> Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study
- DOI:
10.1182/blood-2023-189762 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Ibrahim Aldoss;Ghayas C. Issa;Michael J Thirman;John DiPersio;Martha Arellano;James S. Blachly;Gabriel Mannis;Alexander Perl;David Dickens;Christine M. McMahon;Elie Traer;C. Michel Zwaan;Carolyn Grove;Richard Stone;Paul J Shami;Ioannis Mantzaris;Matthew Greenwood;Neerav Shukla;Branko Cuglievan;Yu Gu - 通讯作者:
Yu Gu
Paul J Shami的其他文献
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{{ truncateString('Paul J Shami', 18)}}的其他基金
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:
7811151 - 财政年份:2009
- 资助金额:
$ 30.29万 - 项目类别:
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:
7759546 - 财政年份:2008
- 资助金额:
$ 30.29万 - 项目类别:
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:
7465286 - 财政年份:2008
- 资助金额:
$ 30.29万 - 项目类别:
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:
7582327 - 财政年份:2008
- 资助金额:
$ 30.29万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 30.29万 - 项目类别:
ROLE OF NITRIC OXIDE IN MYELODYSPLASTIC SYNDROMES
一氧化氮在骨髓增生异常综合征中的作用
- 批准号:
7201437 - 财政年份:2005
- 资助金额:
$ 30.29万 - 项目类别:
GENETIC TARGETS OF NITRIC OXIDE IN LEUKEMIA CELLS
白血病细胞中一氧化氮的基因靶点
- 批准号:
6763232 - 财政年份:2002
- 资助金额:
$ 30.29万 - 项目类别:
GENETIC TARGETS OF NITRIC OXIDE IN LEUKEMIA CELLS
白血病细胞中一氧化氮的基因靶标
- 批准号:
6436675 - 财政年份:2002
- 资助金额:
$ 30.29万 - 项目类别:
GENETIC TARGETS OF NITRIC OXIDE IN LEUKEMIA CELLS
白血病细胞中一氧化氮的基因靶点
- 批准号:
6621777 - 财政年份:2002
- 资助金额:
$ 30.29万 - 项目类别:
NO, GUANYLATE CYCLASE AND IMMUNOTHERAPY OF CANCER
不,鸟苷酸环化酶与癌症免疫治疗
- 批准号:
6129929 - 财政年份:2000
- 资助金额:
$ 30.29万 - 项目类别:
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