Mechanism-based Optimization of Tirapazamine Analogs

替拉扎明类似物的基于机制的优化

• 批准号: 7596336
• 负责人: WILLIAM R WILSON
• 金额: $ 29.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7596336
• 关键词: Accounting; Active Biological Transport; Address; Anoxia; Attention; Benzotriazines; Beta-glucuronidase; Binding; Biological Assay; Bystander Effect; Cell Line; Cells; Characteristics; Chemosensitization; Cisplatin; Clostridium; Computer Simulation; Cytochrome P450; Cytotoxin; DNA; DNA Damage; Development; Diffuse; Diffusion; Drug Delivery Systems; Drug Kinetics; Drug Transport; Enzymes; Escherichia coli; Evaluation; Galactosidase; Generations; Goals; HIF1A gene; Hypoxia; In Vitro; Mass Spectrum Analysis; Maximum Tolerated Dose; Measurement; Measures; Metabolic; Metabolism; Modeling; Mus; NADPH-Ferrihemoprotein Reductase; Necrosis; Nitroreductases; Oxides; Oxidoreductase; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Phase III Clinical Trials; Plasma; Prodrugs; Property; Range; Rate; Recombinants; Screening procedure; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Tumor Tissue; Up-Regulation; analog; base; beta-Galactosidase; cell killing; cytotoxic; cytotoxicity; drug development; drug structure; extracellular; improved; insight; killings; neoplastic cell; novel; pharmacodynamic model; programs; tirapazamine; tumor; tumor xenograft

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.

该项目有三个广泛的目标，每个目标都与该计划的总体目标有关，即开发肿瘤中缺氧细胞的新疗法。所有三个目标的进一步整合主题是使用多细胞层（MCL）培养来量化药物及其活性代谢物的血管外转运。第一个目标是开发一种改进的低氧选择性细胞毒素替拉扎明（TPZ）的类似物，目前正在进行III期临床试验。 该方法基于我们的TPZ空间分辨药代动力学/药效学（PK/PD）模型的见解，该模型明确考虑了血管外转运。该模型表明，可以通过增加血管外扩散系数，优化代谢速率，并提高有助于细胞毒性（λ）的代谢分数来实现活性的大幅增加。我们将使用PK/PD模型来指导化合物的筛选进展，并将评估模型中每个组分的药物结构-活性关系（例如组织中的扩散系数）。我们的方法将测试以下特定假设：（i）DNA靶向可用于提高细胞毒性效力和λ，以及（ii）增加TPZ自由基的细胞内扩散范围是增加λ的进一步策略。第二个目标是表征由重组梭菌在肿瘤的坏死和缺氧区域表达的酶激活前药引起的旁观者效应。这将涉及鉴定由E.大肠杆菌硝基还原酶，β-葡萄糖醛酸酶和β-半乳糖苷酶，并定量血管外运输的活性物质，并产生旁观者杀死，在MCL。第三个目标是确定从靶向HIF-1 α上调的新药筛选中获得的哪些初始“命中”具有足够好的血管外转运特性，以保证进一步的开发。