OPTIMIZATION OF XK469 AGAINST TRANSPLANTED SOLID TUMORS

XK469, 2-[4-（7-氯-2-喹啉氧基）苯氧基]丙酸，是我们实验室评估过的最广泛有效的抗肿瘤药物之一。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合作开发中，预计将于2000年开始临床试验。该项目的目标是获得关于XK469作用机制的深刻信息，并通过(1)XK469同源物和生物同体的综合合成程序来提高先导剂的治疗指数，(a)确定先导化合物的活性中心，即药效团，它负责该药物表现出的高实体肿瘤选择性，(b)改善毒性和宿主恢复时间等局限性。其中包括在小鼠XK469的评估中观察到的；(2)在体外评估所有新合成的类似物，圆盘扩散-软琼脂集落形成-测定每个试剂对白血病，实体瘤和正常细胞的细胞毒性。表现出实体肿瘤选择性的类似物将在荷瘤小鼠中评估其体内功效。然后将在携带多种小鼠和人类肿瘤的小鼠中评估具有高活性的类似物，此外还将利用SCID小鼠用于人类肿瘤。(3)通过合成确证了XK469小鼠尿液代谢产物的质谱结构；(4)利用结构-活性数据建立定量的结构-活性关系，采用比较分子场分析（CoMFA）方法作为设计预测高活性新化合物的基础；(5)对XK469及其类似物的细胞毒作用模式进行了研究探索；(6)确定XK469对选定分子靶点的作用。

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.