Development of the first topo II inhibitor for brain tumors

描述(申请人提供)：我们建议将第一个具有口服活性的拓扑异构酶II抑制剂带入临床用于脑肿瘤的治疗。具体地说，在这个奖项的过程中，我们建议合成5克RTA 769，开发和验证生物分析方法，开发合成RTA 769的GMP程序，制备纯度适合临床前GLP评估和人类临床研究的药物，使用在体小鼠模型来评估RTA 769的药代动力学/代谢，并评估RTA 769在恶性胶质母细胞瘤原位小鼠模型中的口服疗效。我们建议利用REATA和UTMDACC之间的现有关系完成这项研究，UTMDACC已经在类似的18-24个月时间内成功地进行了其他3种UTMDACC化合物的商业开发。我们的技术创新将是开发一种新的抗癌药物，能够在口服后跨越血脑屏障。我们打算在完成SBIR第二阶段的授予后，提交IND并开始第一阶段的临床试验。我们的意图是将RTA 769商业化，用于治疗GBM，尽管这种药物的使用最终将包括其他癌症。RTA 769是使用创新的模块化方法发明的；创建了高亲和力和序列选择性DNA结合剂的文库。有希望的药物被合成和筛选来鉴定这些化合物，它们可以绕过目前可用的Topo II抑制剂的限制。从这个过程中选择了RTA 769，并假设其为1)口服生物利用度，2)跨越血脑屏障，3)穿透肿瘤组织，4)诱导更多的双链DNA损伤，5)较少的心脏毒性和6)更多的细胞凋亡。考虑到治疗像多形性胶质母细胞瘤(GBM)这样威胁生命的疾病的困难，这些新化合物的发明是重要的。基底节细胞瘤是一种常见且致命的脑肿瘤；未经治疗，中位生存期为确诊后3个月。尽管在过去的30年里发展了多模式的治疗策略，但总的生存时间仍然是一年。由于这些肿瘤的侵袭性及其与关键脑结构的关联，完全手术切除这些肿瘤是不可能的：需要放疗和化疗。像RTA 769这样的新制剂的开发是至关重要的，这样我们才能改变这种致命疾病的自然历史。多形性胶质母细胞瘤(GBM)是一种常见的致命性脑肿瘤，尽管在过去的30年里不断发展新的治疗策略，但其生存期不到1年。由于“血脑”屏障，大多数抗癌药物不能进入大脑。在这里，我们建议开发WP769，这是第一种针对脑瘤关键蛋白的“血脑”屏障穿透性抗癌药物，可以口服，应该可以改善这种疾病的总体存活率。

DESCRIPTION (provided by applicant): We proposed to bring the first orally active topoisomerase II inhibitor to the clinic for the treatment of brain tumors. Specifically, in the course of this award we propose to synthesize 5 g of RTA 769, develop and validate bioanalytical methods, develop GMP procedures for the synthesis of RTA 769, preparing drug with a purity suitable for preclinical GLP evaluation and human clinical studies, use an in vivo murine model to asses the pharmacokinetics/metabolism of RTA 769, and evaluate the efficacy of RTA 769 administered orally in an orthotopic mouse model of malignant glioblastoma. We propose to complete this research using an existing relationship between Reata and UTMDACC, which has already been successful in the commercial development of 3 other UTMDACC compounds over a similar 18-24 month timeframe. Our technological innovation will be in the development a novel anticancer agent, capable of cross the blood brain barrier following oral administration. We intend, upon completion of an SBIR Phase II award, to file an IND and begin Phase I clinical trials. It is our intent to commercialize RTA 769 for the treatment of GBM, though the use of this drug would ultimately include other cancers. RTA 769 was invented using an innovative modular approach; libraries of high-affinity and sequence-selective DNA-binding agents were created. Promising agents were synthesized and screened to identify those compounds, which could circumvent the limitations of currently available topo II inhibitors. From this process RTA 769 was selected and hypothesized to 1) be orally bioavailable, 2) cross the blood-brain barrier (BBB), 3) penetrate tumor tissue, 4) induce more double-strand DNA damage, 5) be less cardiotoxic and 6) be more apoptotic. Invention of these novel compounds is important given the difficulty in treating a life threatening disease like glioblastoma multiforme (GBM). GBM is a common and deadly brain tumor; untreated the median survival time is 3 months following diagnosis. Despite the development multimodality therapeutic strategies over the past 3 decades, the overall survival time is still < 1 year. Due to the invasiveness of these tumors and their association with critical brain structures complete surgical ablation of these tumors is impossible: radiation and chemotherapy is required. Development of new agents like RTA 769 is of paramount importance so that we can change the natural history of this lethal disease. Glioblastoma multiforme (GBM) is a common and deadly brain tumor that despite the development new therapeutic strategies over the past 30 years has a survival of less than 1 year. Most anticancer drug cannot cross into the brain due to a "blood-brain" barrier. Here we propose to develop WP769, the first "blood-brain" barrier penetrating anticancer drug targeting a key protein in brain tumors, that can be taken orally and should improve the over all survival of this disease.