Development of JS-K as an anti-leukemic agent

描述(由申请人提供)：本申请是为了响应NOT-OD-09-058号通知而提交的：NIH宣布可为竞争性修订申请提供恢复法案资金。尽管在过去的二十年里，癌症的治疗取得了显著的成就，但癌症仍然是一种具有挑战性的21世纪流行病，需要新的、更有效的药物。我们先前已经证明一氧化氮(NO)可以诱导急性髓系白血病(AML)的分化和凋亡。谷胱甘肽S转移酶(GST)参与多药耐药，在肿瘤细胞株中表达上调。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了这些化合物的文库，从而确定了O2-(2，4-二硝基苯基)1-[(4-乙氧羰基)哌嗪-1-基]二氮-1-正-1，2-二酸酯或JS-K是这类化合物中最具活性的化合物。JS-K在多个实验室的体内外实验中显示出了强大而广泛的抗癌活性。JS-K具有极具挑战性的溶解性和体内稳定性。为了进一步将其推向临床，我们开发了一种独特的P123 Pluronic(R)胶束JS-K配方，该配方解决了这些问题，具有潜在的临床应用价值。在R01 CA129611的资助下，我们正在提炼这种胶束配方，并继续研究Pluronic(R)胶束JS-K在异种移植瘤模型中的药理和体内疗效。为了加快临床开发，我们现在将此竞争性修订申请提交给R01 CA129611。该应用程序的目标是将Pluronic(R)胶束JS-K用于治疗人体试验。我们的假设是，Pluronic(R)胶束JS-K是一种治疗多种癌症的高效且相对无毒的疗法。这一竞争性修订申请将使第一阶段人体安全试验的研究性新药(IND)申请成为可能。在目标1中，我们将进行符合良好制造规范(CGMP)的1公斤JS-K活性药物成分(API)的合成。这项工作将由里奇曼化学公司(www.richmanChemical.com/)完成，该公司是一家备受尊敬的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瓶，并启动一个正式程序来验证瓶的稳定性。这项工作将与金字塔实验室公司(http://pyramidlabs.com)，)一起完成，该公司是一家经验丰富的合同制药剂师。在目标3中，我们将使用良好实验室规范(GLP)程序对两种动物(大鼠和比格犬)进行标准的急性毒理学研究和28天的临床前毒理学研究。这项工作将由犹他大学药学院内的临床前药物评估机构进行。最后，在目标4中，在犹他州教员托马斯·肯尼迪博士的帮助下，我们将总结在这份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癌症新治疗剂的初始人类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。该项目所做的工作将开发一种名为JS-K的癌症治疗新药。

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.