Development of the first topo II inhibitor for brain tumors

开发第一个脑肿瘤拓扑 II 抑制剂

• 批准号: 7327371
• 负责人: RAYMOND J BUDDE
• 金额: $ 12.62万
• 依托单位: HOUSTON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327371
• 关键词: Ablation; Affinity; Antineoplastic Agents; Apoptotic; Asses; Award; Bioavailable; Biodistribution; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Clinic; Clinical Research; DNA Binding Agent; DNA Damage; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug usage; Evaluation; Glioblastoma; Guanosine Monophosphate; Human; In Vitro; Libraries; Life; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Metabolism; Methods; Modeling; Multimodal Imaging; Mus; Natural History; New Agents; Operative Surgical Procedures; Oral Administration; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Poison; Procedures; Process; Production; Proteins; Radiation; Research; Rodent; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specimen; Structure; Therapeutic; Time; Topoisomerase II; Topoisomerase-II Inhibitor; Tumor Tissue; analytical method; chemotherapy; commercialization; ds-DNA; improved; in vivo; inhibitor/antagonist; innovation; mouse model; novel; novel therapeutics; pharmacokinetic model; pre-clinical; scale up; technological innovation; tumor

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.

描述（由申请人提供）：我们提出将第一种口服活性拓扑异构酶II抑制剂用于临床治疗脑肿瘤。具体而言，在本合同的过程中，我们计划合成5 g RTA 769，开发和验证生物分析方法，开发RTA 769合成的GMP程序，制备纯度适合临床前GLP评价和人体临床研究的药物，使用体内鼠模型评估RTA 769的药代动力学/代谢，并评价口服施用RTA 769在恶性胶质母细胞瘤的原位小鼠模型中的功效。我们建议使用Reata和UTMDACC之间的现有关系来完成这项研究，该关系已经在类似的18-24个月时间内成功地商业开发了其他3种UTMDACC化合物。我们的技术创新将是开发一种新型抗癌剂，口服后能够穿过血脑屏障。我们打算在完成SBIR II期研究后，提交IND并开始I期临床试验。我们的目的是将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。有前途的代理人的合成和筛选，以确定这些化合物，这可以规避目前可用的拓扑异构酶II抑制剂的限制。从该过程中选择RTA 769并假设其1）是口服生物可利用的，2）穿过血脑屏障（BBB），3）穿透肿瘤组织，4）诱导更多的双链DNA损伤，5）心脏毒性较小，以及6）凋亡更多。鉴于治疗威胁生命的疾病如多形性胶质母细胞瘤（GBM）的困难，这些新化合物的发明是重要的。GBM是一种常见且致命的脑肿瘤;未经治疗的中位生存时间为诊断后3个月。尽管在过去的30年里发展了多种治疗策略，但总生存时间仍< 1年。由于这些肿瘤的侵袭性及其与关键脑结构的相关性，这些肿瘤的完全手术消融是不可能的：需要放疗和化疗。RTA 769等新药物的开发至关重要，这样我们就可以改变这种致命疾病的自然史。多形性胶质母细胞瘤（GBM）是一种常见且致命的脑肿瘤，尽管在过去30年中开发了新的治疗策略，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WP 769，这是第一种针对脑肿瘤中关键蛋白质的“血脑”屏障穿透抗癌药物，可以口服，并应改善这种疾病的总体生存率。