OPTIMIZATION OF XK469 AGAINST TRANSPLANTED SOLID TUMORS

XK469 针对移植实体瘤的优化

• 批准号: 6628204
• 负责人: JEROME P HORWITZ
• 金额: $ 22.45万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628204
• 关键词: SCID mouse; analog; antineoplastics; apoptosis; benzodiazepine receptor; chemical structure function; cytochrome c; cytotoxicity; drug design /synthesis /production; drug metabolism; drug screening /evaluation; mass spectrometry; mitochondria; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; nonhuman therapy evaluation; quinoxalines; urinalysis

XK469, 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]propionic acid, is among the most broadly active antitumor agents that have been evaluated in our laboratories. The agent is currently in development in a collaborative effort between the National Cancer Institute, the DuPont Corporation and our laboratories with expectations for clinical trial to begin in 2000. The objectives of the project are to elicit incisive information on the mechanism of action of XK469 and to improve the therapeutic index of the lead agent through (1) a comprehensive synthetic program of congeners and bioisosters of XK469 to (a) identify the active centers of the lead compound, i.e., the pharmacophore, which is responsible for the high solid tumor selectivity exhibited by this agent and (b) to improve such limitations as toxicity and host recovery times, among others observed in the evaluation of XK469 in mice; (2) an evaluation of all newly synthesized analogs in an in vitro, disk-diffusion-soft agar-colony-formation-assay to determine the cytotoxicity of each agent against leukemias, solid tumors and normal cells. Analogs that exhibit solid tumor selectivity will be evaluated in tumor-bearing mice for in vivo efficacy. Analogs demonstrating high activity will then be evaluated in mice carrying a variety of tumors of both mouse and human origin, utilizing, in addition, SCID mice for human tumors.; (3) corroboration, through synthesis, of structures assigned by mass spectrometry to mouse-urinary metabolites of XK469; (4) the use of structure-activity data to establish quantitative structure activity relationships, using the methodology of comparative molecular field analysis (CoMFA) as the basis for the design of novel compounds of predicted high activity; (5) an investigative exploration of the modes of cytotoxic action of XK469 and its analogs; and (6) determine the effect of XK469 on selected molecular targets.

XK469，2-[4-(7-氯-2-喹喔啉氧基)苯氧基]丙酸，是我们实验室评估过的活性最广泛的抗肿瘤药物之一。 该药物目前正在国家癌症研究所、杜邦公司和我们的实验室的共同努力下进行开发，预计临床试验将于 2000 年开始。该项目的目标是获取有关 XK469 作用机制的深入信息和通过 (1) XK469 同系物和生物等排体的综合合成程序来提高先导药物的治疗指数，以 (a) 确定先导化合物的活性中心，即药效团，它是该药物表现出的高实体瘤选择性的原因，并且（b）改善毒性和宿主恢复时间等限制，以及在小鼠中评估 XK469 时观察到的其他限制； (2)在体外盘扩散软琼脂集落形成测定中评估所有新合成的类似物，以确定每种药剂针对白血病、实体瘤和正常细胞的细胞毒性。 将在荷瘤小鼠中评估表现出实体瘤选择性的类似物的体内功效。 然后，将在携带多种小鼠和人类来源的肿瘤的小鼠中评估表现出高活性的类似物，此外还利用针对人类肿瘤的 SCID 小鼠。 (3) 通过合成证实 XK469 小鼠尿液代谢物的质谱结构； （4）利用构效数据建立定量的构效关系，利用比较分子场分析（CoMFA）的方法论作为设计预测高活性的新型化合物的基础； (5) XK469及其类似物的细胞毒作用模式的研究探索； (6)确定XK469对选定分子靶标的作用。