Molecular Design of Ras Farnesyltransferase Inhibitors

癌基因ras存在于多种哺乳动物癌细胞中，其编码蛋白ras是抗癌药物的重要靶点。RAS蛋白末端半胱氨酸残基的法尼基转移酶(FTase)是RAS蛋白功能所必需的。鉴于RAS蛋白是一种锌酶，本研究的目的是通过合成有机化学家、FTase酶学家和癌基因和细胞信号转导研究人员的合作，设计和合成锌螯合剂，以寻找新型FTase抑制剂。2001年，美国加州大学洛杉矶分校的Fuyuhiko Tamanoi，美国国家卫生研究所的Terence R.Burke，杜克大学的Patrick J.Casey，除了该项目的研究人员大冢、冈原、山崎、冈原、山崎、大冢、冈原、山崎、大冢、冈原、山崎、冈本、Umezawa和Imoto外，还有David R.Corey(德克萨斯大学达拉斯西南医学中心)、John S.Lazo(匹兹堡大学)、Veeraswamy Manne(百时美施贵宝药物研究所)。2001年7月27日和28日在熊本召开了一次国际研讨会(美日化学-生物界面联合研讨会)，报告和讨论了本研究项目的研究结果。2001年的研究结果总结如下：(I)由二甲氨基吡啶和组胺侧链组成的各种合成螯合剂对法尼基转移酶突变体有抑制作用；(Ii)组氨酸-吡啶-组氨酸配体被发现是一种有用的增敏剂，可用于肿瘤细胞的热疗。(3)阐明了RAS的法尼化与法尼基转移酶之间的关系；(4)研究了法尼基转移酶抑制剂的临床应用；(5)合成了Grb2SH结构域的抑制剂。

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.