OPTIMIZATION OF XK469 AGAINST TRANSPLANTED SOLID TUMORS

XK 469，2-[4-（7-氯-2-喹啉基氧基）苯氧基]丙酸，是我们实验室评价的最广泛活性的抗肿瘤剂之一。 目前，国家癌症研究所、杜邦公司和我们的实验室正在合作开发这种药物，预期临床试验将于2000年开始。该项目的目标是获得关于XK 469作用机制的深刻信息，并通过（1）XK 469的同源物和生物电子等排体的综合合成计划来提高先导化合物的治疗指数，以（a）鉴定先导化合物的活性中心，即，药效团，其负责该试剂所表现出的高实体瘤选择性，和（B）改善诸如毒性和宿主恢复时间等限制，尤其是在小鼠中评价XK 469时观察到的限制;（2）在体外圆盘扩散软琼脂集落形成测定中评价所有新合成的类似物，以确定每种试剂对白血病的细胞毒性，实体瘤和正常细胞。 将在荷瘤小鼠中评价表现出实体瘤选择性的类似物的体内功效。 然后在携带多种小鼠和人源肿瘤的小鼠中评价表现出高活性的类似物，此外，还利用SCID小鼠评价人肿瘤。(3)通过合成确证XK 469的小鼠尿代谢产物的质谱归属结构：（4）使用结构-活性数据建立定量结构活性关系，使用比较分子场分析（CoMFA）方法学作为设计具有预测高活性的新化合物的基础;（5）XK 469及其类似物的细胞毒性作用模式的研究性探索;和（6）确定XK 469对选定的分子靶点的作用。

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.