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

描述（由申请人提供）：尽管在过去二十年中取得了显著成就，但癌症仍然是一种具有挑战性的世纪流行病，需要新的更有效的药物。众所周知，一氧化氮（NO）可以杀死癌细胞而不伤害正常的骨髓细胞，但由于其降低血压的作用，迄今为止尚未直接用于治疗癌症。JSK Therapeutics（JSKT）设计了一类二醇二氮烯鎓前药，其在谷胱甘肽-S-转移酶催化的反应中与谷胱甘肽相互作用后释放NO，与正常细胞相比，谷胱甘肽-S-转移酶在癌症中以显著更高的浓度表达。JSKT筛选了这些化合物的库，并确定了一种JS-K是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对整个“NCI 60-cell”屏幕都是活跃的。JS-K在多个实验室中对实体瘤和血液恶性肿瘤具有有效和广泛的抗癌活性，但对正常骨髓没有毒性，这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对急性髓性白血病、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。在这种有前途的疗法上已经开始了重要的工作，并且已经表明JS-K难以溶解并且在体内具有短的半衰期。先前的NIH资助为这些挑战提供了解决方案：已经开发了用于JS-K的稳定的纳米级P123 Pluronic（R）胶束静脉注射（IV）制剂，并且目前正在按照良好生产规范生产P123 Pluronic（R）胶束中的1 kg JS-K的规模化生产和制剂。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）进行所需的标准急性和亚慢性临床前动物毒理学研究，以支持向FDA成功提交研究性新药（IND）申请。JSKT假设P123 Pluronic（R）胶束JS-K将被证明在治疗人类癌症所需的治疗剂量下无毒。在I期，JSKT将完成3项可交付成果：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（艾姆斯）试验; 3）起草JS-K IND申请的化学和生产章节。在第二阶段，JSKT将完成2个额外的可交付成果：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）完成犬中JS-K的急性IV毒理学研究和大鼠和犬中JS-K的28天亚慢性IV毒理学研究。完成该项目后，JSKT将拥有所有必要的药理学、毒理学和生产信息，以提交一份成功的IND，在犹他湖城的亨斯迈癌症研究所开始I期胶束JS-K人体安全性试验。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，通过更少痛苦，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益处。 公共卫生相关性： 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，更具选择性和可测量的毒性更小的机制杀死这些癌症，使其完全与当今世界相关。这种新药更进一步：它将通过提供比目前更有效、更少痛苦的治疗，改善癌症患者、其护理人员和家庭的生活质量。

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.