BIOCHEMICAL, BIOLOGICAL, AND ANTITUMOR EFFICACY OF RAS FTASE INHIBITORS

RAS FT酶抑制剂的生化、生物学和抗肿瘤功效

• 批准号: 6203311
• 负责人: SAID M SEBTI
• 金额: $ 21.22万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203311
• 关键词: 3T3 cells; DNA replication; SDS polyacrylamide gel electrophoresis; antineoplastics; athymic mouse; cell cycle; chemical synthesis; cooperative study; disease /disorder model; drug design /synthesis /production; enzyme activity; enzyme inhibitors; enzyme structure; epidermal growth factor; farnesyl compound; gene mutation; geranyl compound; growth factor receptors; human tissue; nonhuman therapy evaluation; oncogenes; protein purification; tissue /cell culture; transferase

The overall long-term objective of this NCDDG is to develop novel anti- cancer drugs based on inhibition of Ras farnesylation, a lipid modification required for plasma membrane association and malignant transformation activity of Ras. The overall goal of Program #2 within the NCDDG is to evaluate and develop Ras farnesyltransferase (FTase) inhibitors into pharmacological agents selective for human tumors with aberrant Ras function. The specific aims of Program #2 are: 1) to investigate the structural requirements of inhibition of farnesylation. The ability of the molecules synthesized by Program #1 to inhibit Ras FTase in vitro and Ras processing/plasma membrane association in intact cells will be investigated, 2) to determine the selectivity of the molecules identified in specific aim 1) towards inhibition of farnesylation. The ability of FTase inhibitors to inhibit geranylgeranyltransferase I (GGTase I) and GGTase II, two closely related enzymes, as well as the ability of inhibitors to block geranylgeranylation and farnesylation of several proteins in cultured cells will be evaluated, 3) to investigate the selectivity of FTase-specific inhibitors to inhibit DNA synthesis and proliferation and to reverse ras-dependent transformation. Cells transformed with oncogenes that use a ras-dependent pathway and a ras-independent pathway as well as cells transformed with oncogenes that encode farnesylated, geranylgeranylated or myristylated Ras will be used to evaluate this selectivity issue, 4) to determine the antitumor efficacy in a nude mouse xenograft model of FTase-specific inhibitors against human tumors that express mutated ras oncogenes, 5) to determine the selectivity of Ftase inhibitors to block in vivo tumor growth of human tumors expressing K-, N- and H-ras oncogene mutations and 6) to evaluate the antitumor efficacy of FTase inhibitors against human tumors with an upregulated Ras function due to activation of events upstream of Ras as well as human tumors that overexpress non-mutated Ras. The work described in Program #2 will enhance our understanding of the mechanism of inhibition of FTase and the selective use of this molecular target to interfere with in vivo tumor growth. Furthermore, the synergy born out of the efforts of the interrelated and interdependent Programs #1, #2 and #3 of this NCDDG will lead to the development of selective anti-cancer drugs against human tumors with aberrant Ras function.

该NCDG的总体长期目标是发展新型的抗 基于抑制Ras Farnesylation的癌症药物，一种脂质 质膜关联和恶性所需的修改 RAS的转化活性。 计划2的总体目标 NCDG将评估和开发Ras Farnesylsylsferase（FTase） 抑制剂进入药理学剂对人类肿瘤的选择性 异常RAS功能。 程序＃2的具体目的是：1） 研究抑制法尼化的结构要求。 程序＃1合成的分子抑制RAS的能力 完整的体外和RAS加工/质膜关联 将研究细胞，2）确定的选择性 特定目标中鉴定出的分子1） 法尼化。 FTase抑制剂抑制的能力 香烷基凝血酶转移酶I（GGTase I）和GGTase II，两个密切相关的 酶，以及抑制剂阻断黄烷基凝聚力的能力 将评估培养细胞中几种蛋白质的法尼化，并将评估 3）研究FTase特异性抑制剂抑制的选择性 DNA合成和增殖，并逆转RAS依赖性 转型。 细胞用使用RAS依赖性的致癌基因转化 途径和不依赖RAS的途径以及与RAS的细胞一起转化 编码法尼的癌基因，黄烷基化或肉豆蔻酰化的Ras 将用于评估此选择性问题，4）确定 FTase特异性的裸小鼠异种移植模型中的抗肿瘤功效 对表达突变Ras癌基因的人肿瘤的抑制剂，5） 确定FTase抑制剂对阻断体内肿瘤的选择性 表达K-，N和H-RAS癌基因突变的人类肿瘤的生长以及 6）评估FTase抑制剂对人的抗肿瘤功效 由于事件的激活，具有上调RAS功能的肿瘤 RAS的上游以及过表达非突变RA的人类肿瘤。 节目2中描述的工作将增强我们对 抑制FTase的机制和该分子的选择性使用 靶向干扰体内肿瘤生长的靶标。 此外，协同作用 源于相互关联和相互依存的程序的努力 NCDDG的＃1，＃2和＃3将导致选择性的发展 针对异常RAS功能的人类肿瘤的抗癌药。