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
• 负责人: Paul J Shami
• 金额: $ 106.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2013-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811151
• 关键词: Achievement; Acute; Acute Myelocytic Leukemia; Animals; Antineoplastic Agents; Apoptosis; Blood; Cancer Hospital; Canis familiaris; Chemicals; Chemistry; Clinic; Clinical; Clinical Pharmacology; Clinical Trials; Collaborations; Contracts; Cyclic GMP; Data; Development; Disodium Salt Nitroprusside; Dose; Drug Delivery Systems; Drug Design; Drug Formulations; Epidemic; Faculty; Family; Funding; Glutathione; Glutathione S-Transferase; Goals; Half-Life; Human; Hypotension; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Libraries; Life; Malignant Neoplasms; Manufacturer Name; Medicine; Methods; Micelles; Modeling; Multi-Drug Resistance; National Cancer Institute; Nitric Oxide; Nitric Oxide Synthase; Normal Cell; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacy Schools; Phase; Phase I Clinical Trials; Pluronics; Polymers; Preclinical Drug Evaluation; Problem Solving; Procedures; Prodrugs; Property; Proteins; Public Health; Rattus; Reaction; Recovery; Relaxation; Research; Research Proposals; Safety; Screening procedure; Services; Signal Transduction Pathway; Solubility; Soluble Guanylate Cyclase; Speed; Sterility; Sulfhydryl Compounds; System; Therapeutic; Therapeutic Agents; Toxicology; Translational Research; Treatment Efficacy; United States National Institutes of Health; Universities; Up-Regulation; Utah; Vascular Smooth Muscle; Vasodilator Agents; Vial device; Work; Writing; aqueous; cancer cell; cancer therapy; clinical toxicology; design; diazeniumdiolate; dinitrophenyl; experience; good laboratory practice; in vitro activity; in vivo; member; nanoscale; novel; novel therapeutics; pre-clinical; professor; programs; public health relevance; response; safety study; tumor xenograft

DESCRIPTION (provided by applicant): This application is submitted in response to Notice Number NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Despite notable achievements in its treatment over the past two decades, cancer remains a challenging twenty-first century epidemic demanding new, more effective drugs. We have previously shown that nitric oxide (NO) induces differentiation and apoptosis in acute myeloid leukemia (AML). Glutathione S -transferases (GST) are involved in multi-drug resistance and are upregulated in cancer cell 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 and broad anti-cancer activity in vitro and in vivo in multiple laboratories. JS-K has challenging solubility properties and in vivo stability properties. To further its advancement to the clinic, we have developed a unique P123 Pluronic(r) micellar JS-K formulation which solves these problems with its potential clinical use. With funding from R01 CA129611 we are refining this micellar formulation and are continuing to study the pharmacology and in vivo efficacy of Pluronic(r) micellar JS-K in xenograft tumor models. To speed clinical development we now submit this Competitive Revision Application to R01 CA129611. The goal of this application is to bring Pluronic(r) micellar JS -K to therapeutic human trials. Our hypothesis is that Pluronic(r) micellar JS-K is a highly effective and relatively non-toxic therapy for multiple cancers. This Competitive Revision Application will make possible progression to an Investigational New Drug (IND) application for Phase I human safety trials. In Aim 1, we will perform synthesis of 1 kg JS-K Active Pharmaceutical Ingredient (API) compliant with Good Manufacturing Practices (cGMP). This work will be done by Richman Chemical, Inc., (www.richmanchemical.com/), a well -respected cGMP contract manufacturer pharmaceutical grade therapeutic compounds. In Aim 2 we will formulate JS-K and Pluronic(r) P123 polymers into sterile unit dose vials using cGMP methods, and initiate a formal program to validate vial stability. This work will be done with Pyramid Laboratories, Inc. (http://pyramidlabs.com), an experienced contract pharmaceutical formulator. In Aim 3 we will perform standard acute and 28-day pre-clinical toxicology studies in two species (rats and Beagle dogs) using Good Laboratory Practice (GLP) procedures. This work will be performed by the Preclinical Drug Evaluation Facility within the University of Utah School of Pharmacy. Finally, in Aim 4, with the assistance of Dr. Thomas Kennedy, a Utah faculty member who has previously authored successful applications, we will summarize the work accomplished in this Competitive Revision Application, and submit it as part of an IND to perform at the Huntsman Cancer Hospital initial human Phase I safety trials of P123 Pluronic(r) micellar JS -K as an exciting new therapeutic agent for cancer. PUBLIC HEALTH RELEVANCE: There is a great need for new drugs to treat Cancer. Work done in this project will develop a new drug called JS-K for the treatment of Cancer.

描述（由申请人提供）：本申请是为了响应通知编号NOT-OD-09-058：NIH宣布恢复法案资金可用于竞争性修订申请而提交的。 尽管在过去的二十年里，癌症的治疗取得了显著的成就，但癌症仍然是二十一世纪具有挑战性的流行病，需要新的、更有效的药物。我们以前已经表明，一氧化氮（NO）诱导分化和凋亡的急性髓细胞白血病（AML）。谷胱甘肽S -转移酶（GST）参与多药耐药性，并在癌细胞分离株中上调。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已在多个实验室的体外和体内显示出有效和广泛的抗癌活性。JS-K具有挑战性的溶解性和体内稳定性。为了进一步推进其临床应用，我们开发了一种独特的P123 Pluronic（r）胶束JS-K制剂，该制剂通过其潜在的临床应用解决了这些问题。在R 01 CA 129611的资助下，我们正在改进这种胶束制剂，并继续研究Pluronic（r）胶束JS-K在异种移植肿瘤模型中的药理学和体内功效。为了加快临床开发，我们现在向R 01 CA 129611提交了该竞争修订申请。这项申请的目的是将Pluronic（r）胶束JS-K用于治疗性人体试验。我们的假设是，Pluronic（r）胶束JS-K是一种高效且相对无毒的多种癌症治疗方法。这一竞争性修订申请将有可能进展为I期人体安全性试验的研究性新药（IND）申请。在目标1中，我们将按照药品生产质量管理规范（cGMP）合成1 kg JS-K活性药物成分（API）。这项工作将由里奇曼化学公司完成，（www.richmanchemical.com/），一家备受尊敬的cGMP合同制造商，生产药用级治疗化合物。在目标2中，我们将使用cGMP方法将JS-K和Pluronic（r）P123聚合物配制成无菌单位剂量小瓶，并启动正式程序以验证小瓶稳定性。这项工作将由Pyramid Laboratories，Inc.完成。(http：pyramidlabs.com），一位经验丰富的合同药物配方设计师。在目标3中，我们将使用药物非临床研究质量管理规范（GLP）程序在两个种属（大鼠和比格犬）中进行标准急性和28天临床前毒理学研究。这项工作将由犹他州大学药学院的临床前药物评价机构进行。最后，在目标4中，在托马斯肯尼迪博士（犹他州的一名教员，他以前曾成功撰写过申请）的帮助下，我们将总结本竞争性修订申请中完成的工作，并将其作为IND的一部分提交，以便在亨斯迈癌症医院进行P123 Pluronic（r）胶束JS-K作为一种令人兴奋的新型癌症治疗剂的初始人体I期安全性试验。 公共卫生相关性：非常需要治疗癌症的新药。在这个项目中所做的工作将开发一种名为JS-K的新药用于治疗癌症。