Preclinical Development of JS-K, a Novel NO-Generating Prodrug for Cancer

JS-K（一种新型 NO 生成癌症前药）的临床前开发

• 批准号: 8926544
• 负责人: Gregory John Johnson
• 金额: $ 14.28万
• 依托单位: JSK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-23 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926544
• 关键词: Achievement; Acute; Acute Myelocytic Leukemia; Animals; Antineoplastic Agents; Bacteria; Biological Assay; Bone Marrow; Bone Marrow Cells; Cancer Patient; Canis familiaris; Capital Financing; Cardiovascular system; Cells; Chemistry; Chromosome abnormality; Chronic; Cities; Clinical; Clinical Trials; Collaborations; Complement; Correlative Study; Cyclic GMP; Development; Dose; Drug Design; Drug Formulations; Drug Kinetics; Drug Stability; Drug usage; Epidemic; Family; Family Caregiver; Funding; Future; Glutathione; Glutathione S-Transferase; Goals; Grant; Half-Life; Hematologic Neoplasms; Human; Hypotension; Injection of therapeutic agent; Institutes; Intravenous; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Libraries; Liquid Chromatography; Liquid substance; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Micelles; Multiple Myeloma; Mus; Mutation; National Cancer Institute; Neurologic; Nitric Oxide; Nitric Oxide Synthase; Non-Small-Cell Lung Carcinoma; Normal Cell; One-Step dentin bonding system; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacy facility; Phase; Pluronics; Preclinical Drug Evaluation; Primary carcinoma of the liver cells; Procedures; Prodrugs; Production; Property; Protocols documentation; Quality of life; Rapid Access to Intervention Development; Rattus; Reaction; Recovery; Relaxation; Rivers; Safety; Schedule; Signal Transduction Pathway; Small Business Innovation Research Grant; Sodium Chloride; Solid Neoplasm; Soluble Guanylate Cyclase; Solutions; Testing; Therapeutic; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Utah; Vascular Smooth Muscle; Vasodilator Agents; Water; Work; Writing; Xenograft Model; anticancer activity; aqueous; base; cancer cell; cancer therapy; college; commercialization; design; diazeniumdiolate; dinitrophenyl; effective therapy; fighting; good laboratory practice; improved; in vitro activity; in vivo; killings; liquid chromatography mass spectrometry; mass spectrometer; nanoscale; novel; pre-clinical; programs; scale up; tandem mass spectrometry; tumor

DESCRIPTION (provided by applicant): Despite notable achievements over the past two decades, cancer remains a challenging 21st century epidemic demanding new, more effective drugs. Nitric oxide (NO) is well known to kill cancer cells without harming normal bone marrow cells, but until now has not been used directly to treat cancer because of its effect to lower blood pressure. JSK Therapeutics (JSKT) has designed a class of diazeniumdiolate prodrugs that release NO upon interaction with glutathione in a reaction catalyzed by glutathione-S-transferase, which is expressed at significantly higher concentrations in cancer compared to normal cells. JSKT has screened a library of these compounds and has identified one, JS-K, as the most active compound of this family. In the Rapid Access to Intervention Development (RAID) program at the NCI, JS-K is active against the entire "NCI 60-cell" screen. JS-K has potent and broad anticancer activity against solid tumors and hematologic malignancies in multiple laboratories but shows no toxicity against normal bone marrow, making it critically important to the future of cancer therapy. In mouse xenograft models of human tumors, JS-K is highly effective against acute myeloid leukemia, prostate cancer, hepatocellular carcinoma, multiple myeloma and non-small cell lung cancer. Significant work has begun on this promising therapy and has shown that JS-K is difficult to solubilize and has a short half-life in vivo. Previous NIH funding has allowed a solution for these challenges: a stable nanoscale P123 Pluronic(R) micelle intravenous (IV) formulation for JS-K has been developed, and scale- up production and formulation of 1 kg of JS-K in P123 Pluronic(R) micelles is currently under production in compliance with Good Manufacturing Practices. JSKT submits this Fast Track Phase I/II SBIR application to perform the standard acute and subchronic pre-clinical animal toxicology studies needed using Good Laboratory Practices (GLP) to support a successful Investigational New Drug (IND) application to the FDA. JSKT hypothesizes that P123 Pluronic(R) micelle JS-K will prove non-toxic in therapeutic doses needed to treat cancer in humans. In Phase I, JSKT will accomplish 3 deliverables: 1) perform acute IV toxicology of JS-K in rats; 2) perform bacterial mutagenicity (Ames) testing; and 3) draft the chemistry and manufacturing section for a JS-K IND application. In Phase II, JSKT will accomplish 2 additional deliverables: 1) develop and validate using GLP procedures a sensitive LS/MS/MS assay for measuring JS-K in biologic fluids; and 2) complete acute IV toxicology studies of JS-K in dogs and 28-day subchronic IV toxicology studies of JS-K in rats and dogs. Upon completion of this project, JSKT will have all the essential pharmacology, toxicology and manufacturing information to submit a successful IND to begin Phase I safety trials of micelle JS-K in humans at the Huntsman Cancer Institute in Salt Lake City, UT. Commercialization of this novel cancer fighting drug, JS-K, will establish a new paradigm in cancer therapy, improve the quality of life for cancer patients and their families with less painful, more effective treatments, and provide a sustainable benefit worldwide.

描述(申请人提供)：尽管在过去的二十年里取得了显著的成就，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。众所周知，一氧化氮(NO)可以在不损害正常骨髓细胞的情况下杀死癌细胞，但由于其降低血压的作用，到目前为止还没有直接用于治疗癌症。JSK Treeutics(JSK Treateutics)设计了一类重氮尿苷前药，在谷胱甘肽-S-转移酶的催化下，与谷胱甘肽相互作用时释放NO，该酶在癌细胞中的表达浓度比正常细胞高得多。JSKT已经筛选了这些化合物的文库，并确定其中一种，JS-K，是该家族中最有活性的化合物。在NCI的快速介入开发(RAID)计划中，JS-K在整个“NCI 60细胞”屏幕上处于活动状态。JS-K在多个实验室对实体瘤和血液系统恶性肿瘤具有强大而广泛的抗癌活性，但对正常骨髓没有毒性，因此它对未来的癌症治疗至关重要。在小鼠人肿瘤异种移植模型中，JS-K对急性髓系白血病、前列腺癌、肝细胞癌、多发性骨髓瘤和非小细胞肺癌具有高效的治疗作用。关于这种有希望的疗法的重要工作已经开始，并表明JS-K很难溶解，在体内的半衰期很短。美国国立卫生研究院之前的资金已经为这些挑战提供了解决方案：用于JS-K的稳定的纳米级P123 Pluronic(R)胶束静脉注射(IV)配方已经开发出来，目前正在按照良好制造规范的要求，在P123 Pluronic(R)胶束中扩大生产和配制1公斤JS-K。JSKT提交此Fast Track I/II期SBIR申请，以执行使用良好实验室操作规范(GLP)进行的标准急性和亚慢性临床前动物毒理学研究，以支持向FDA成功提交研究新药(IND)申请。JSKT假设P123 Pluronic(R)胶束JS-K在治疗人类癌症所需的治疗剂量下将被证明是无毒的。在第一阶段，JSKT将完成3项交付成果：1)在大鼠身上进行JS-K的急性IV毒理学；2)进行细菌诱变性(Ames)测试；以及3)为JS-K IND应用起草化学和制造部分。在第二阶段，JSKT将实现另外两项交付成果：1)使用GLP程序开发和验证灵敏的LS/MS/MS分析方法，用于测量生物液体中的JS-K；以及2)完成JS-K在狗身上的急性IV毒理学研究和28天的JS-K在大鼠和狗身上的亚慢性IV毒理学研究。该项目完成后，JSKT将拥有所有必要的药理学、毒理学和制造信息，以提交成功的IND，以便在德克萨斯州盐湖城的亨斯迈癌症研究所开始胶束JS-K在人类身上的I期安全性试验。这种新型抗癌药物JS-K的商业化将建立癌症治疗的新范式，以更少的痛苦和更有效的治疗改善癌症患者及其家人的生活质量，并在全球范围内提供可持续的好处。