Clinical Development of JS-K for the Treatment of Cancer

项目描述- JSK Therapeutics（JSKT）直接进入II期应用 一氧化氮（NO）是一种潜在的强大的抗癌疗法。自发产生NO的药物不能 由于NO的多效性作用，NO可用于治疗恶性肿瘤。特别是，NO是一种有效的血管扩张剂 导致低血压。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的试剂。在与拉里·基弗博士在国家 癌症研究所的Paul Shami博士已经开发出这样一种药物，使用释放NO的化合物， 在谷胱甘肽S-转移酶（GST）催化的反应中与谷胱甘肽（GSH）相互作用。这种药物 设计利用了GST在恶性细胞中的过表达。一种铅化合物被鉴定为 本族活性物质：O2-（2，4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]二氮烯-1-鎓-1，2-二醇盐，或JS- K. JS-K在体外和体内具有有效和广谱的抗癌活性。因为挑战 溶解性和稳定性，Shami实验室开发了一种使用Pluronic® P123的JS-K配方 胶束在非GLP犬毒理学研究中，P123胶束（P123/JS-K）中配制的JS-K耐受性良好 而不引起低血压。JS-K对恶性细胞具有直接细胞毒性，并且也是 血管生成JS-K是一个非常有效的消费者的抗氧化剂三肽谷胱甘肽（GSH），使 恶性细胞对氧化应激特别敏感。JS-K对正常造血细胞无毒性 细胞JS-K与阿糖胞苷对急性髓性白血病（AML）具有协同作用，与硼替佐米对急性髓性白血病（AML）具有协同作用。 多发性骨髓瘤（MM）。最近的数据表明，JS-K可能使MM细胞对以下物质的细胞毒性作用敏感： 自然杀伤（NK）细胞，提高了与新的免疫调节剂协同组合的可能性。 剂.在cGMP条件下生产1千克JS-K活性药物成分。JSK Therapeutics（JSKT）的成立是为了引领JS-K的商业化。美国食品药品 政府已批准JS-K用于AML和MM适应症的孤儿药认定。JSKT计划 开发JS-K最初用于治疗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提交研究性新药（IND）申请。在4个目标中， 将开发并验证用于测量生物基质中JS-K的分析方法; GLP 大鼠和犬的毒理学研究，使用重现前瞻性临床试验的给药方案 将在大鼠中进行GLP肺和中枢神经系统毒理学研究; 并将在犬中进行GLP心血管系统毒理学研究。在该项目完成时， JSKT将向FDA提交IND申请，以便开始I期临床试验，用于复发性/难治性 AML和MM。这将允许与成熟的制药公司合作或获得风险投资 投资，以完成JS-K的临床开发和商业化，从而增加了一个有力的 我们的医疗设备中的一种新药，旨在减少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.