Molecular Design of Ras Farnesyltransferase Inhibitors

Ras 法尼基转移酶抑制剂的分子设计

基本信息

批准号：
11694297
负责人：
OTSUKA Masami
金额：
$ 5.82万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694297/
关键词：
man-made chelator farnesyltransferase oncogene Ras protein

项目摘要

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.

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。法尼基转移酶（FTase）对Ras蛋白末端半胱氨酸残基的法尼基化对于Ras蛋白的功能至关重要。考虑到Ras蛋白是一种锌酶，本研究的目的是设计和合成锌螯合剂合成有机化学家、FTase酶学家以及癌基因和细胞信号研究人员合作寻找新型FTase抑制剂。2001年进行了多元化研究美国同事 Fuyuhiko Tamanoi（加州大学洛杉矶分校）、Terrence R. Burke（国立卫生研究院）、Patrick J. Casey（杜克大学）、David R. Corey（德克萨斯大学西南医学中心）达拉斯）、John S. Lazo（匹兹堡大学）、Veeraswamy Manne（百时美施贵宝制药研究所）以及该项目的研究人员 Otsuka、大河原、山崎、冈本、梅泽和井本。 2001年7月27日至28日在熊本召开了一次国际研讨会（美国-日本化学-生物界面联合研讨会），报告和讨论了本研究项目的研究成果。2001年的成果总结如下：（ i) 法呢基转移酶突变体被由二甲氨基吡啶和组胺侧链组成的各种合成螯合剂抑制，(ii) A组氨酸-吡啶-组氨酸配体被发现可用作癌细胞系高温治疗的敏化剂。 (iii)阐明Ras法尼基化与法尼基转移酶之间的关系，(iv)研究法尼基转移酶抑制剂的临床应用，(v)合成Grb2SH结构域抑制剂。