Taccalonolides: Mechanisms of Action and Cellular Resistance

他卡酮内酯：作用机制和细胞耐药性

• 批准号: 8530175
• 负责人: Susan L Mooberry
• 金额: $ 24.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530175
• 关键词: Advanced Malignant Neoplasm; Affect; Binding; Binding Sites; Biological; Biological Markers; Breast Cancer Model; Cell Death; Cell Line; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Data; Defect; Doxorubicin; Drug Design; Drug resistance; Drug usage; Epothilones; Event; Goals; In Vitro; Interphase; Interruption; Ixabepilone; Lead; Ligands; Microtubule Bundle; Microtubule stabilizing agent; Microtubules; Mitotic; Mitotic spindle; Molecular Mechanisms of Action; Morphology; Multi-Drug Resistance; Mus; Mutation; Neoplasm Metastasis; Paclitaxel; Pharmaceutical Preparations; Plants; Property; Reaction; Research; Resistance; Series; Signal Pathway; Signal Transduction; Site; Structure-Activity Relationship; Tacca; Taxane Compound; Techniques; Testing; Time; Tubulin; cancer cell; cancer therapy; clinically relevant; docetaxel; drug development; improved; in vivo; laulimalide; malignant breast neoplasm; novel; pharmacophore; polymerization; research study; resistance mechanism; response; structural biology; taxane; trafficking; tumor

DESCRIPTION (provided by applicant): Microtubule stabilizers are valuable drugs used in the treatment of cancer. The focus of this project is a new class of plant-derived microtubule stabilizers, the taccalonolides. The taccalonolides have distinct effects on interphase microtubule bundling, mitotic spindle morphology and mitotic signaling pathways. Potent new taccalonolides have been identified for the first time and they robustly polymerize purified tubuli indicating a direct interaction with tubulin/microtubules. The tubulin polymerization experiments also indicate that the taccalonolides interact with tubulin in a manner different from other microtubule stabilizers. Our preliminary data suggest that the taccalonolides bind within a unique site on tubulin. All of the taccalonolides overcome clinically relevant mechanisms of drug resistance and the taccalonolides A and E have in vivo antitumor activity against a paclitaxel and doxorubicin-resistant murine model of breast cancer. Comprehensive studies are proposed to identify the tubulin binding site of the taccalonolides, the functional significance of this bining and how this interrupts mitotic and interphase signaling downstream. These studies are expected to identify a new tubulin binding site or pharmacophore for stabilizing microtubules. The first aim will identify the binding site of the taccalonolides on tubulin/microtubules utilizin complementary structural biology approaches. The second aim describes the functional significance of the taccalonolide interaction with tubulin/microtubules biochemically and in cells. This aim will identify the effects of the potent taccalonolides on purified tubulin and on cellular microtubule dynamics. We anticipate that interruption of microtubule dynamics leads to mitotic signaling and interphase microtubule trafficking defects and ultimately cell death. The last aim will examine the structure-activity relationships of the taccalonolides to identify the specific chemical moieties necessary for optimal biological activities. Information gained from these studies will elucidate the chemical and biological properties of this new class of microtubule stabilizers. This is expected to lead to the identification of a new microtubule stabilizer binding site on tubulin that will provide new opportunities for rational drug development with the possibility of a unique spectrum of activity.

描述(申请人提供)：微管稳定剂是用于治疗癌症的有价值的药物。本项目的重点是一种新型的植物来源的微管稳定剂--塔卡洛内酯。塔卡罗内酯对间期微管束、有丝分裂纺锤体形态和有丝分裂信号通路有明显的影响。首次发现了有效的新塔卡洛内酯，它们强健地聚合了纯化的小管，表明它们与微管/微管直接相互作用。微管蛋白聚合实验还表明，塔卡洛内酯与微管蛋白以不同于其他微管稳定剂的方式相互作用。我们的初步数据表明，塔卡洛内酯结合在微管蛋白上的一个独特的位置。所有的塔卡洛内酯都克服了临床上相关的耐药机制，而且塔卡洛内酯A和E在体内对紫杉醇和阿霉素耐药的乳腺癌小鼠模型具有抗肿瘤活性。人们建议进行全面的研究，以确定塔卡洛内酯的微管蛋白结合部位，这种结合的功能意义，以及这种结合如何中断下游的有丝分裂和间期信号。这些研究有望确定一种新的微管蛋白结合部位或药效团以稳定微管。第一个目标是利用互补的结构生物学方法确定塔卡洛内酯在微管/微管上的结合位置。第二个目的描述了塔卡洛内酯与微管/微管的相互作用在生化和细胞中的功能意义。 这一目标将确定有效的塔卡洛内酯对纯化的微管蛋白和细胞的影响。 微管动力学。我们预计，微管动力学的中断会导致有丝分裂信号和间期微管运输缺陷，最终导致细胞死亡。最后一个目标将研究塔卡洛内酯的结构-活性关系，以确定最佳生物活性所必需的特定化学部分。从这些研究中获得的信息将阐明这种新型微管稳定剂的化学和生物学特性。这有望导致一种新的微管稳定剂结合的鉴定 这将为合理的药物开发提供新的机会，并可能产生独特的活性谱。