Anticancer redox inhibitor,Pleurotin

抗癌氧化还原抑制剂、侧耳素

• 批准号: 6879258
• 负责人: LYNN KIRKPATRICK
• 金额: $ 19.36万
• 依托单位: PROLX PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879258
• 关键词: NAD(P)H oxidoreductase; SCID mouse; antineoplastics; cell growth regulation; cell line; colon neoplasms; dosage; drug administration routes; enzyme inhibitors; fungal antigens; high performance liquid chromatography; hypoxia inducible factor 1; kidney neoplasms; lung neoplasms; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; ovary neoplasms; oxidation reduction reaction; pharmacokinetics; thioredoxin; ultraviolet spectrometry; vascular endothelial growth factors

DESCRIPTION (provided by applicant): One in every four deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake preclinical evaluation of a novel clinical candidate that targets the thioredoxin reductase enzyme, for the eventual use of this agent as a therapy against solid tumor cancers. ProIX Pharmaceuticals has demonstrated there is strong evidence for the following: 1) The redox protein thioredoxin-1 (Trx-1) is necessary for the hypoxia-induced increase in HIF-1 alpha, a critical regulator of increased angiogenesis and decreased apoptosis in solid tumors. 2) Trx-1 causes an increase in HIF-1 alpha transactivating activity and expression of VEGF as well as HIF-1 alpha staining and angiogenesis in experimental tumors in vivo. 3) The expression of Trx-1 is increased in many human primary tumors where it is associated with aggressive tumor growth and decreased patient survival. 4) Trx-1 is reduced by NADPH in the presence of the flavoprotein thioredoxin reductase (TR). 5) The fungal metabolite pleurotin is a potent inhibitor of TR and also inhibits the hypoxia induced increase of HIF-1 alpha in cancer of cell lines and xenografts. Preliminary results show that pleurotin has anti-tumor activity in spontaneous and tumor xenograft models. The objectives of this Phase I study to be conducted by ProIX Pharmaceuticals are: 1) to determine whether inhibition of TR translates to provide anti-tumor activity in vivo; 2) to determine whether the anti-tumor activity is accompanied by decreased HIF-1 alpha and VEGF production in vivo; 3) to identify the optimal dosing and scheduling of pleurotin and determine the pharmacokinetic profile of the agent. The results of this application are anticipated to lead to a Phase II application that will undertake the pre-clinical toxicological and pharmaceutical development of pluerotin as a TR inhibitor and anti-cancer drug. ProIX has the exclusive license to develop this agent as an anti-cancer drug.

描述（由申请人提供）： 在美国，每四人中的一个死亡中有一个是由于癌症造成的。在美国，整体癌症药物市场超过20亿美元。非常需要鉴定新颖和选择性的小分子癌症疗法。 该提案旨在对靶向硫氧还蛋白还原酶酶的新型临床候选者进行临床前评估，以最终将这种药物用作对实体瘤癌的治疗。 Proix Pharmaceuticals已证明有强大的证据表明：1）氧化还原蛋白硫氧还蛋白-1（TRX-1）对于缺氧诱导的HIF-1 Alpha的增加是必要的，HIF-1 Alpha是血管生成增加和降低实体瘤的凋亡的关键调节剂。 2）TRX-1导致HIF-1α反式激活活性和VEGF的表达以及体内实验性肿瘤中的HIF-1α染色和血管生成。 3）在许多人类原发性肿瘤中，TRX-1的表达与侵袭性肿瘤生长和患者生存降低有关。 4）在存在黄素蛋白硫氧还蛋白还原酶（TR）的情况下，NADPH降低了TRX-1。 5）真菌代谢产物胸膜素是TR的有效抑制剂，也抑制缺氧在细胞系和异种移植物癌中诱导的HIF-1α升高。初步结果表明，胸膜素在自发和肿瘤异种移植模型中具有抗肿瘤活性。 该阶段研究的目标是由Proix Pharmaceuticals进行的：1）确定TR抑制是否转化以在体内提供抗肿瘤活性； 2）确定抗肿瘤活性是否伴随着体内HIF-1α和VEGF产生的降低； 3）确定胸膜蛋白的最佳剂量和调度，并确定剂的药代动力学特征。预计该应用的结果将导致II期应用，该应用将进行pluerotin蛋白作为TR抑制剂和抗癌药物的临床前毒理学和药物发育。 Proix拥有将该代理作为抗癌药物开发的独家许可。