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

描述（由申请人提供）：尽管在过去的二十年中取得了显著的成就，癌症仍然是21世纪具有挑战性的流行病，需要新的，更有效的药物。众所周知，一氧化氮（NO）能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，迄今为止还没有直接用于治疗癌症。JSK Therapeutics （JSKT）设计了一类重氮二酸酯前药，在谷胱甘肽- s -转移酶催化的反应中与谷胱甘肽相互作用释放NO，与正常细胞相比，癌症细胞中NO的表达浓度明显更高。JSKT筛选了这些化合物的一个文库，并鉴定出该家族中活性最强的化合物JS-K。在NCI的快速介入开发（RAID）项目中，JS-K对整个“NCI 60细胞”筛查都是有效的。在多个实验室中，JS-K对实体肿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，这对未来的癌症治疗至关重要。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有很高的疗效。这项有前景的治疗已经开始了重要的工作，并表明JS-K难以溶解，并且在体内半衰期短。先前NIH的资助为这些挑战提供了解决方案：一种稳定的纳米级P123 Pluronic(R)胶束静脉注射（IV）制剂已经开发出来，1公斤P123 Pluronic(R)胶束的JS-K的规模化生产和制剂目前正在按照良好生产规范进行生产。JSKT提交快速通道I/II期SBIR申请，以执行标准的急性和亚慢性临床前动物毒理学研究，需要使用良好实验室规范（GLP）来支持成功的临床新药（IND）申请。JSKT假设P123 Pluronic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I期，JSKT将完成3个可交付成果：1)在大鼠体内进行JS-K的急性静脉毒理学研究；2)进行细菌诱变性（Ames）检测；3)起草JS-K IND申请的化学和制造部分。在II期，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分析；2)完成犬类JS-K的急性静脉毒理学研究和大鼠、犬类JS-K的28天亚慢性静脉毒理学研究。该项目完成后，JSKT将获得所有必要的药理学、毒理学和生产信息，以提交一份成功的IND，在美国犹他州盐湖城的亨茨曼癌症研究所开始胶束JS-K的人体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方法改善癌症患者及其家属的生活质量，并为全球提供可持续的利益。

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.