A Hypoxia Activated HIF-1 & Inhibitor for Cancer Therapy

描述(由申请人提供)： ProlX制药公司，一家专注于氧化还原目标的公司 抗癌治疗已确定PX-478是一种新的低氧诱导剂 低氧因子(HIF)抑制剂和低氧旁观者抗癌剂。首字母 第一阶段SBIR提案，旨在合成和评估 会在缺氧的肿瘤环境中被激活，前提是 PX-478被低氧癌细胞选择性激活的证据 一种抑制HIF-1α和血管内皮生长因子升高的药物 (血管内皮生长因子)由细胞产生。此第二阶段SBIR提案的目标是 是通过更广泛的临床前开发来移动PX-478。这个 该提案的具体目标是：1)合成三种盐类制剂 PX-478，并对其物理化学性质和性能进行评价 每种制剂的药代动力学，以选择制剂和候选制剂 生物利用度研究；2)扩大PX-478的动物模型评价和 基于抑制HIF/VEGF的生物终点检测方法的建立 3)PX-478对啮齿动物的GLP毒理学评价 狗的种类。此第二阶段SBIR的结论将参见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。 建议的商业应用： 在美国，每五例死亡中就有一例死于癌症。整体抗癌药物市场超过 在美国为20亿美元。有必要确定新的和选择性的基于小分子的癌症治疗方法。这项提议寻求进行一种新型的抗缺氧/缺氧旁观者PX-478的全面临床前开发，并启动一项第一阶段临床试验，最终将其用于癌症治疗。

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.