Molecular Design of Ras Farnesyltransferase Inhibitors

癌基因ras存在于许多哺乳动物癌细胞中，其编码的蛋白Ras是抗癌药物的重要靶点。Ras蛋白是一种锌酶，因此本研究的目的是设计合成锌螯合剂，寻找新型的法尼基转移酶抑制剂，并将其应用于Ras蛋白的研究中。2001年，美国同行Fuyuhiko Tamanoi（加州大学，洛杉矶）、Terrence R. Burke（国家卫生研究所）、帕特里克J.凯西（杜克大学）、大卫R.科里（德克萨斯大学西南医学中心达拉斯），约翰S。Lazo（匹兹堡大学）、Veeraswamy Manne（百时美施贵宝制药研究所）以及本项目的研究者Otsuka、Okawara、Yamasaki、Okamoto、Umezawa和Imoto。国际研讨会（美日化学生物界面联合研讨会）在熊本召开（2001年7月27日及28日），汇报及讨论本研究计划的研究结果。2001年的研究结果概述如下：（i）法尼基转移酶突变体被由二甲基氨基吡啶和组胺侧链组成的各种合成螯合剂抑制，（ii）发现组氨酸-吡啶-组氨酸配体可用作癌细胞系的热处理的敏化剂。(iii)（iv）法尼基转移酶抑制剂的临床应用研究;（v）Grb 2SH结构域抑制剂的合成。

Oncogene ras is found in many mammalian cancer cells and the encoded protein Ras is an important target for anticancer agents. The farnesylation of the terminal cystein residue of the Ras protein by farnesyltransferase (FTase) is essential for the function of the Ras protein.Considering that the Ras protein is a zinc enzyme, the objective of the present research is to design and synthesize zinc chelating agents to find novel inhibitors of FTase by a collaboration of synthetic organic chemists, FTase enzymologists, and researchers of oncogene and cellular signaling.In 2001 a diversified research was carried out by the participation of US colleagues, Fuyuhiko Tamanoi (University of California, Los Angeles), Terrence R. Burke (National Institute of Health), Patrick J. Casey (Duke University), David R. Corey (University of Texas Southwestern Medical Center at Dallas), John S. Lazo(University of Pittsburgh), Veeraswamy Manne (Bristol-Myers Squibb Pharmaceutical Research Institute) in addition to the Investigators of this project, Otsuka, Okawara, Yamasaki, Okamoto, Umezawa, and Imoto. An international symposium (US-Japan Joint Symposium on Chemistry-Biology Interface) was held in Kumamoto (July 27 and 28, 2001) to report and discuss the research results of the present research project.The results of 2001 were summarized as follows : (i) Farnesyltransferase mutants were inhibited by various synthetic chelators consisting of a dimethylaminopyridine and histamine side chains, (ii) A histidine-pyridine-histidine ligand was found to be a useful as a sensitizer for the hyperthermic treatment of cancer cell lines. (iii) The relationships betweenthe farnesylation of Ras and farnesyltransferase were elucidated, (iv) Clinical application of farnesyltransferase inhibitors was studied, (v) Inhibitors of Grb2SH domain were synthesized.