A Hypoxia Activated HIF-1 & Inhibitor for Cancer Therapy

描述（由申请人提供）： ProlX Pharmaceuticals是一家专注于开发氧化还原靶点的公司， 抗癌疗法，已确定PX-478作为一种新的缺氧诱导 因子（HIF）抑制剂和缺氧旁观者抗癌剂。初始 第一阶段SBIR提案，旨在合成和评估 在缺氧的肿瘤环境中被激活， 证据表明PX-478被缺氧癌细胞选择性激活， HIF-1 α和血管内皮生长因子增加的抑制剂 （VEGF）的产生。第二阶段SBIR提案的目标是 是将PX-478进行更广泛的临床前开发。的 该方案的具体目标是：1）合成三种盐制剂， PX-478并评价其物理化学性质和性能， 每种制剂的药代动力学，以选择制剂的候选物， 生物利用度研究; 2）扩大PX-478的动物模型评价， 开发基于HIF/VEGF抑制的生物学终点测定 表达; 3）在啮齿动物中进行PX-478的GLP毒理学评价， 狗的种类第二阶段SBIR的结论将看到ProIX 制药公司将PX-478通过完整的临床前开发转移到IND 提交给FDA。 拟定商业应用： 在美国，每五个死亡中就有一个死于癌症。 整体癌症药物市场超过 美国20亿美元。 非常需要鉴定新的和选择性的基于小分子的癌症疗法。 该提案旨在进行新型抗HIF/低氧旁观者PX-478的全面临床前开发，并启动I期临床试验，以最终用作癌症治疗。

DESCRIPTION (provided by applicant): ProlX Pharmaceuticals, a company focusing on redox targets for development of anti-cancer therapies, has identified PX-478 as a novel hypoxia inducible factor (HIF) inhibitor and hypoxic bystander anti-cancer agent. The initial Phase I SBIR proposal, with aims to synthesize and evaluate novel agents that would be activated within a hypoxic tumor environment, provided strong evidence that PX-478 is selectively activated by hypoxic cancer cells and is an inhibitor of increased HIF-1 alpha and vascular endothelial growth factor (VEGF) production by the cells. The objective of this Phase II SBIR proposal is to move PX-478 through more extensive pre-clinical development. The specific aims of the proposal are: 1) to synthesize three salt preparations of PX-478 and to evaluate the physical chemical properties and properties and pharmacokinetics of each preparation to select a candidate for formulation and bioavailability studies; 2) to expand animal model evaluation of PX-478 and develop a biological endpoint assay based upon inhibition of HIF/VEGF expression; 3) to perform GLP toxicological evaluation of PX-478 in rodent and dog species. The conclusion of this Phase II SBIR will see ProIX Pharmaceuticals move PX-478 through complete pre-clinical development to IND submission to the FDA. PROPOSED COMMERCIAL APPLICATION: One in every five deaths in the US is doe to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is a significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake full preclinical development of a novel anti HIF/hypoxic bystander, PX-478, and initiate a Phase I clinical trial for its eventual use as a therapy against cancer.