A Hypoxia Activated HIF-1 & Inhibitor for Cancer Therapy

缺氧激活的 HIF-1

• 批准号: 6918549
• 负责人: LYNN KIRKPATRICK
• 金额: $ 65万
• 依托单位: PROLX PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918549
• 关键词: SCID mouse; antineoplastics; chemical structure function; clinical research; clinical trial phase I; cytotoxicity; dogs; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; human subject; human therapy evaluation; hypoxia inducible factor 1; neoplasm /cancer pharmacology; nitrogen mustard; patient oriented research; pharmacokinetics

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.

描述（由申请人提供）： ProlX Pharmaceuticals，一家专注于开发氧化还原靶标的公司 抗癌疗法，已确定 PX-478 是一种新型缺氧诱导剂 因子（HIF）抑制剂和缺氧旁观者抗癌剂。最初的 第一阶段 SBIR 提案，旨在合成和评估新型药物 将在缺氧肿瘤环境中被激活，只要有强大的 有证据表明 PX-478 被缺氧癌细胞选择性激活，并且 HIF-1 α 和血管内皮生长因子增加的抑制剂 (VEGF) 由细胞产生。第二阶段 SBIR 提案的目标 是让 PX-478 通过更广泛的临床前开发。这 该提案的具体目标是：1）合成三种盐制剂 并评价PX-478的物理化学性质和性能 每种制剂的药代动力学，以选择候选制剂和 生物利用度研究； 2) 扩大PX-478的动物模型评价和 开发基于 HIF/VEGF 抑制的生物终点测定 表达; 3) 对PX-478在啮齿类动物中进行GLP毒理学评价 狗的种类。 ProIX 将于第二阶段 SBIR 结束 制药公司将 PX-478 通过完整的临床前开发转入 IND 向 FDA 提交。 拟议的商业应用： 在美国，五分之一的死亡是死于癌症。 整体抗癌药物市场规模超过 美国20亿美元。 迫切需要确定新颖且选择性的基于小分子的癌症疗法。 该提案旨在对新型抗 HIF/缺氧旁观者 PX-478 进行全面的临床前开发，并启动 I 期临床试验，以最终将其用作癌症治疗。