Clinical Development of JS-K for the Treatment of Cancer

项目描述-JSK Treateutics(JSKT)直接应用于第二阶段 一氧化氮(NO)是一种潜在的抗癌有效疗法。自发产生一氧化氮的药物不能 由于NO的多效性，被用于治疗恶性肿瘤。特别是，一氧化氮是一种有效的血管扩张剂 随之而来的低血压。为了使基于NO的癌症治疗成为可能，有必要开发 优先向恶性细胞递送NO的药物。与拉里·基弗博士合作在国家 癌症研究所的保罗·沙米博士已经开发出这样一种药物，它使用的是不会释放的化合物。 谷胱甘肽S转移酶催化的反应中与谷胱甘肽的相互作用。这种药 设计利用了GST在恶性细胞中的过度表达。一种铅化合物被确定为最 该家族的活性：O2-(2，4-二硝基苯基)1-[(4-乙氧羰基)哌嗪-1-基]二氮-1-二氮杂-1，2-二酸，或JS- K.JS-K在体内外均具有较强的广谱抗癌活性。因为具有挑战性 为了提高JS-K的溶解性和稳定性，Shami实验室使用Pluronic®P123开发了JS-K配方 胶束。在P123胶束中配制的JS-K(P123/JS-K)在非GLP犬毒理学研究中耐受性良好 而不会引起低血压。JS-K对肿瘤细胞有直接的细胞毒作用，也是一种抑制肿瘤生长的药物。 血管生成。JS-K是一种非常有效的抗氧化剂三肽谷胱甘肽(GSH)的消费者，呈现 恶性细胞特别容易受到氧化应激的影响。JS-K对正常造血功能无毒性 细胞。JS-K与阿糖胞苷治疗急性髓系白血病有协同作用，与硼替佐米联合治疗急性髓系白血病有协同作用 多发性骨髓瘤(MM)。最近的数据表明，JS-K可能使MM细胞敏化其细胞毒作用 自然杀伤(NK)细胞，提高了与新型免疫调节剂协同结合的可能性 探员们。在cGMP条件下生产1公斤JS-K活性药物成分。JSK 治疗公司(JSKT)的成立是为了领导JS-K的商业化。美国的食品和药品 美国政府已批准JS-K的孤儿药物指定用于AML和MM的适应症。JSKT计划 初步开发JS-K用于治疗AML和MM。该项目的目标是完成临床前 动物毒理学研究需要向FDA提交研究新药(IND)申请。在4个目标中， 将开发和验证生物基质中JS-K的分析方法；GLP 大鼠和狗的毒理学研究，使用重现预期临床的给药时间表 将进行GLP肺和中枢神经系统毒理学研究； 并将在狗身上进行GLP心血管系统毒理学研究。在这个项目完成时， JSKT将向FDA提交IND申请，以启动复发/难治的I期临床试验 AML和MM。这将允许与老牌制药公司合作或获得合资企业。 投资以完成JS-K的临床开发和商业化，从而增加一个强有力的 我们医院的新药旨在减轻与癌症有关的疼痛和痛苦。

PROJECT DESCRIPTION — JSK Therapeutics (JSKT) Direct to Phase II Application Nitric oxide (NO) is a potentially powerful therapy against cancer. Spontaneous NO-generating drugs cannot be used to treat malignancies because of the pleiotropic effects of NO. In particular, NO is a potent vasodilator with resultant hypotension. In order to make NO-based cancer therapy possible, it is necessary to develop agents that deliver NO preferentially to malignant cells. In collaboration with Dr. Larry Keefer at the National Cancer Institute, Dr. Paul Shami has developed such a drug using compounds that release NO upon interaction with glutathione (GSH) in a reaction catalyzed by Glutathione S-Transferases (GST). This drug design exploits the over-expression of GST in malignant cells. A lead compound was identified as the most active of this family: O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl]diazen-1-ium-1,2-diolate, or JS- K. JS-K has potent and broad-spectrum anti-cancer activity in vitro and in vivo. Because of challenging solubility and stability properties, the Shami lab has developed a formulation for JS-K using Pluronic® P123 micelles. JS-K formulated in P123 micelles (P123/JS-K) was well tolerated in a non-GLP dog toxicology study without the induction of hypotension. JS-K is directly cytotoxic to malignant cells and also an inhibitor of angiogenesis. JS-K is a very efficient consumer of the anti-oxidant tripeptide glutathione (GSH), rendering malignant cells particularly susceptible to oxidative stress. JS-K is not toxic towards normal hematopoietic cells. JS-K is synergistic with cytarabine against acute myeloid leukemia (AML) and with bortezomib against multiple myeloma (MM). Recent data suggest that JS-K may sensitize MM cells to the cytotoxic effect of natural killer (NK) cells, raising the possibility of synergistic combinations with novel immunomodulatory agents. One kilogram of JS-K Active Pharmaceutical Ingredient was produced under cGMP conditions. JSK Therapeutics (JSKT) was founded to lead commercialization of JS-K. The United States Food and Drug Administration has granted orphan drug designation for JS-K for the indications of AML and MM. JSKT plans to develop JS-K initially for the treatment of AML and MM. The objective of this project is to complete pre-clinical animal toxicology studies needed to file an Investigational New Drug (IND) application with the FDA. In 4 aims, an analytical method for the measurement of JS-K in biologic matrices will be developed and validated; GLP toxicology studies in rats and dogs using a schedule of administration that reproduces the prospective clinical schedule will be conducted; GLP lung and central nervous system toxicology studies will be conducted in rats; and a GLP cardiovascular system toxicology study will be conducted in dogs. At the completion of this project, JSKT will submit an IND application to the FDA in order to start Phase I clinical trials for relapsed/refractory AML and MM. This will allow partnering with an established pharmaceutical company or obtaining venture investment in order to complete the clinical development and commercialization of JS-K, thus adding a potent new drug to our armamentarium aimed at diminishing the pain and suffering associated with cancer.