Anticancer redox inhibitor,Pleurotin

描述（由申请人提供）： 在美国，四分之一的死亡是由于癌症造成的。美国癌症药物市场总体规模超过 20 亿美元。非常需要确定新颖且选择性的基于小分子的癌症疗法。 该提案旨在对一种针对硫氧还蛋白还原酶的新型临床候选药物进行临床前评估，以最终将该药物用作实体瘤癌症的治疗方法。 ProIX Pharmaceuticals 已证明有以下强有力的证据：1) 氧化还原蛋白硫氧还蛋白-1 (Trx-1) 对于缺氧诱导的 HIF-1 α 增加是必需的，HIF-1 α 是实体瘤中血管生成增加和细胞凋亡减少的关键调节因子。 2)Trx-1引起体内实验肿瘤中HIF-1α反式激活活性和VEGF表达以及HIF-1α染色和血管生成的增加。 3) Trx-1 的表达在许多人类原发性肿瘤中增加，与侵袭性肿瘤生长和患者生存率降低有关。 4) 在黄素蛋白硫氧还蛋白还原酶 (TR) 存在的情况下，Trx-1 被 NADPH 还原。 5) 真菌代谢物侧耳素是TR的有效抑制剂，并且还抑制细胞系和异种移植物中缺氧诱导的HIF-1α的增加。初步结果表明侧耳素在自发和肿瘤异种移植模型中具有抗肿瘤活性。 ProIX Pharmaceuticals 进行的这项 I 期研究的目的是： 1) 确定 TR 的抑制是否转化为提供体内抗肿瘤活性； 2)确定抗肿瘤活性是否伴随着体内HIF-1α和VEGF产生的减少； 3) 确定侧耳素的最佳剂量和时间安排，并确定药物的药代动力学特征。该申请的结果预计将导致 II 期申请，该申请将承担普鲁罗素作为 TR 抑制剂和抗癌药物的临床前毒理学和药物开发。 ProIX 拥有开发该药物作为抗癌药物的独家许可。

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.