Anticancer redox inhibitor,Pleurotin

描述（由申请人提供）： 在美国，每四个死亡中就有一个是由癌症引起的。在美国，整个癌症药物市场超过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。 该提案旨在对靶向硫氧还蛋白还原酶的新型临床候选药物进行临床前评价，以最终将该药物用作实体瘤癌症的治疗。 ProIX制药公司已经证明，有强有力的证据表明：1）氧化还原蛋白硫氧还蛋白-1（Trx-1）是缺氧诱导的HIF-1 α增加所必需的，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导致体内实验肿瘤中HIF-1 α反式激活活性和VEGF表达以及HIF-1 α染色和血管生成增加。3)Trx-1的表达在许多人类原发性肿瘤中增加，其中其与侵袭性肿瘤生长和降低的患者存活率相关。4)在黄素蛋白硫氧还蛋白还原酶（TR）存在下，Trx-1被NADPH还原。5)真菌代谢物pleurotin是TR的有效抑制剂，并且还抑制细胞系和异种移植物的癌症中缺氧诱导的HIF-1 α的增加。初步结果表明，pleurotin在自发和肿瘤异种移植模型中具有抗肿瘤活性。 由ProIX Pharmaceuticals进行的这项I期研究的目的是：1）确定TR的抑制是否转化为体内抗肿瘤活性; 2）确定抗肿瘤活性是否伴随着体内HIF-1 α和VEGF产生的减少; 3）确定pleurotin的最佳剂量和时间表，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pluerotin作为TR抑制剂和抗癌药物的临床前毒理学和药物开发。ProIX拥有开发这种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.