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

基本信息

批准号：
8424339
负责人：
THOMAS PRESTON KENNEDY
金额：
$ 92.76万
依托单位：
JSK THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-23 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424339
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 public health relevance scale up tandem mass spectrometry tumor

项目摘要

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. PUBLIC HEALTH RELEVANCE: This project will continue the development of a highly effective new drug called JS-K, which will treat and kill multiple cancers. JS-K will kill these cancers by a new, more selective and measurably less toxic mechanism, making it entirely relevant to today's world. This new drug then goes one step further: it will improve the quality of life for cancer patients, their caregivers and families by providing a significantly more effective and less painful therapy than is currently available.

描述（由申请人提供）：尽管过去二十年取得了显着的成就，但癌症仍然是 21 世纪充满挑战的流行病，需要新的、更有效的药物。众所周知，一氧化氮 (NO) 可以杀死癌细胞而不伤害正常骨髓细胞，但由于其具有降低血压的作用，迄今为止尚未直接用于治疗癌症。 JSK Therapeutics (JSKT) 设计了一类二氮烯二醇前药，在谷胱甘肽-S-转移酶催化的反应中与谷胱甘肽相互作用时释放 NO，与正常细胞相比，谷胱甘肽在癌症中的表达浓度明显更高。 JSKT 筛选了这些化合物的库，并确定了一种 JS-K 作为该家族中最活跃的化合物。在 NCI 的快速干预开发 (RAID) 计划中，JS-K 积极针对整个“NCI 60 细胞”屏幕。在多个实验室中，JS-K 对实体瘤和血液恶性肿瘤具有有效且广泛的抗癌活性，但对正常骨髓没有毒性，这使其对癌症治疗的未来至关重要。在人类肿瘤的小鼠异种移植模型中，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非常有效。关于这种有希望的疗法的重要工作已经开始，并表明 JS-K 难以溶解且体内半衰期短。之前的 NIH 资助已经为这些挑战提供了解决方案：用于 JS-K 的稳定纳米级 P123 Pluronic(R) 胶束静脉注射 (IV) 制剂已经开发出来，并在 P123 Pluronic 中扩大生产和配制 1 公斤 JS-K (R) 胶束目前正在按照良好生产规范进行生产。 JSKT 提交此快速通道 I/II 期 SBIR 申请，以使用良好实验室规范 (GLP) 进行标准急性和亚慢性临床前动物毒理学研究，以支持向 FDA 成功提交研究性新药 (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证明是无毒的。在第一阶段，JSKT 将完成 3 个可交付成果：1）在大鼠中进行 JS-K 的急性 IV 毒理学研究； 2）进行细菌致突变性（Ames）测试； 3) 起草 JS-K IND 申请的化学和制造部分。在第二阶段，JSKT 将完成 2 个额外的交付成果：1) 使用 GLP 程序开发和验证用于测量生物液体中 JS-K 的灵敏 LS/MS/MS 测定法； 2) 完成JS-K在犬中的急性IV毒理学研究和JS-K在大鼠和犬中的28天亚慢性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，以成功提交 IND，在犹他州盐湖城的亨斯曼癌症研究所开始人体胶束 JS-K 的 I 期安全试验。这种新型抗癌药物 JS-K 的商业化将建立癌症治疗的新范例，通过更少痛苦、更有效的治疗来改善癌症患者及其家人的生活质量，并为全世界带来可持续的利益。公共健康相关性：该项目将继续开发一种名为 JS-K 的高效新药，该药物将治疗和杀死多种癌症。 JS-K 将通过一种新的、更具选择性且毒性明显更低的机制杀死这些癌症，使其与当今世界完全相关。这种新药更进一步：它将通过提供比目前可用的治疗方法更有效且痛苦更少的治疗方法来改善癌症患者、他们的护理人员和家人的生活质量。