Mechanism-based Optimization of Tirapazamine Analogs

替拉扎明类似物的基于机制的优化

• 批准号: 6985628
• 负责人: WILLIAM R WILSON
• 金额: $ 14.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985628
• 关键词: Clostridium; NAD(P)H oxidoreductase; analog; angiogenesis inhibitors; antineoplastics; athymic mouse; beta galactosidase; beta glucuronidase; chemical structure function; cisplatin; clinical research; combination therapy; cytotoxicity; drug design /synthesis /production; drug metabolism; gene delivery system; gene therapy; human tissue; hypoxia; neoplasm /cancer; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplastic cell; nonhuman therapy evaluation; tirapazamine; transcription factor

This Project has three broad goals, each of which relate to the overall objective of this Program to develop novel therapies for hypoxic cells in tumors. A further integrating theme across all three goals is use of multicellular layer (MCL) cultures to quantify extravascular transport of drugs and their active metabolites. The first goal is to develop an improved analog of the hypoxia-selective cytotoxin tirapazamine (TPZ), which is currently in phase III clinical trial. The approach is based on insights from our spatially-resolved pharmacokinetic/pharmacodynamic (PK/PD) model for TPZ, which explicitly takes extravascular transport into account. This model demonstrates that large gains in activity could be achieved by increasing extravascular diffusion coefficients, optimizing rates of metabolism, and improving the fraction of metabolism that contributes to cytotoxicity (lambda). We will use the PK/PD model to guide advancement of compounds through screening, and will evaluate drug structure-activity relationships for each component of the model (e.g. diffusion coefficient in tissue). Our approach will test the specific hypotheses that (i) DNA targeting can be used to improve the cytotoxic potency and lambda, and (ii) increasing the intracellular diffusion range of the TPZ radical is a further strategy for increasing lambda. The second goal is to characterize bystander effects resulting from activation of prodrugs by enzymes expressed by recombinant clostridia in necrotic and hypoxic regions of tumors. This will involve the identification of active metabolites resulting from activation of prodrugs by E. coli nitroreductase, beta-glucuronidase and beta-galactosidase, and to quantify extravascular transport of the active species, and the resulting bystander killing, in MCLs. The third goal is to identify which of the initial "hits" from a screen for novel drugs targeting HIF-1alpha upregulation have good enough extravascular transport properties to warrant further development.

该项目具有三个广泛的目标，每个目标都与该计划的整体目标有关，以开发肿瘤中缺氧细胞的新疗法。在所有三个目标中的进一步整合主题是使用多细胞层（MCL）培养物来量化药物的血管外运输及其活性代谢物。第一个目标是开发改进的低氧选择性细胞毒素Tirapazamine（TPZ）的类似物，该类似物目前正在III期临床试验中。 该方法基于我们的空间分辨药代动力学/药效动力学（PK/PD）模型的见解，该模型明确考虑了血管外运输。该模型表明，通过增加血管外扩散系数，优化代谢率以及改善有助于细胞毒性（LAMBDA）的代谢分数，可以通过增加血管外扩散系数，优化新陈代谢速率来实现大量活动。我们将使用PK/PD模型通过筛选来指导化合物的发展，并评估模型每个组件的药物结构 - 活性关系（例如，组织中的扩散系数）。我们的方法将检验（i）DNA靶向可用于提高细胞毒性和lambda的特定假设，并且（ii）增加TPZ自由基的细胞内扩散范围是增加lambda的进一步策略。第二个目标是表征由肿瘤坏死和低氧区域中重组梭子表达的酶激活前药引起的旁观者作用。这将涉及鉴定由大肠杆菌硝基细胞酶，β-葡萄糖醛酸酶和β-半乳糖苷酶激活前药引起的活性代谢产物，以及量化活性物种的血管外转运，以及所得的旁观者在MCL中杀死的旁观者。第三个目标是确定靶向HIF-1Alpha上调的新型药物的最初“命中”中的哪些“命中”具有足够好的血管外运输特性，以保证进一步发展。