PROTEIN KINASE INHIBITORS

蛋白激酶抑制剂

基本信息

批准号：
2094995
负责人：
DAVID G HANGAUER
金额：
$ 17.73万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 1995-06-30
项目状态：
已结题

项目摘要

The specific aims of this proposal are to explore potential new protein kinase inhibitor designs, some of which may be broadly applied and others of which may have enhanced selectivity for individual kinases. The new inhibitor designs will be tested against three growth factor receptor tyrosine kinases, eight oncogene-related tyrosine kinases, three isozymes of protein kinase C, and cAMP-dependent protein kinase. This research could lead to inhibitors which would be useful for investigating the biological significance of individual protein kinases and ultimately for various therapeutic applications. The most promising potential therapeutic uses may be in the anti-cancer and anti-AIDS areas for isozyme-selective protein kinase C inhibitors and in the anti-cancer and immunomodulator areas for tyrosine kinase inhibitors. Other potential therapeutic applications include myosin light chain kinase inhibitors as anti- hypertensive agents. Our long term objectives are to utilize our most successful inhibitor designs to prepare prototype anti-cancer, anti-AIDS, immunosuppressant and anti-hypertensive protein kinase inhibitors which may be used as lead compounds for a more extensive research program aimed at developing clinically useful drugs. This proposal is focused upon four structural classes of inhibitor designs which are appended to small peptides and may extend into the catalytic region of the kinase active sites, yet bind non-competitively with ATP or ADP. The appendages are intended to enhance binding by interacting with the catalytic residues, Mg2+ ATP or Mg2+ ADP. A first level of inhibitor selectivity will be achieved by choosing the peptide sequence based upon the substrate selectivity for the individual kinase(s). A second level of selectivity will be sought by widely testing the inhibitor designs in anticipation of differing abilities of the individual kinases to accommodate the unnatural appendages. This anticipation is precedented by literature reports showing selectivities on the order of 10-5,000 fold among isozymes of particular enzymes with substrate-derived inhibitors.

该建议的具体目的是探索潜在的新蛋白质激酶抑制剂设计，其中一些可能广泛应用其中可能对单个激酶具有增强的选择性。新的抑制剂设计将针对三个生长因子受体进行测试酪氨酸激酶，八个与癌基因相关的酪氨酸激酶，三个同工酶蛋白激酶C和cAMP依赖性蛋白激酶的。这项研究可能导致抑制剂，这对于研究个体蛋白激酶的生物学意义，最终各种治疗应用。最有希望的潜在治疗使用可能是在抗癌和抗AIDS区域的同工酶选择性区域蛋白激酶C抑制剂以及抗癌和免疫调节剂中酪氨酸激酶抑制剂的区域。其他潜在的治疗性应用包括肌球蛋白轻链激酶抑制剂作为抗高血压剂。我们的长期目标是最多利用我们的成功的抑制剂设计以制备原型抗癌，抗AIDS，免疫抑制剂和抗高血压蛋白激酶抑制剂，可能用作更广泛的研究计划的铅化合物开发临床上有用的药物。该建议集中于四个结构性抑制剂设计类别附加到小肽上，可能延伸到催化激酶活性位点的区域，但与ATP或 adp。附属物旨在通过与催化残基Mg2+ ATP或MG2+ ADP。抑制剂的第一级选择性将通过基于单个激酶的底物选择性。第二级将通过广泛测试抑制剂设计来寻求选择性对单个激酶不同能力的期待容纳不自然的附属物。这种期待先于文献报告显示了10-5,000倍的订单的选择性在具有底物衍生抑制剂的特定酶的同工酶中。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The design, synthesis and activity of pentapeptide pp60c-src inhibitors containing L-phosphotyrosine mimics.

含有 L-磷酸酪氨酸模拟物的五肽 pp60c-src 抑制剂的设计、合成和活性。

DOI：
10.1111/j.1399-3011.1998.tb00424.x
发表时间：
1998
期刊：
The journal of peptide research : official journal of the American Peptide Society.
影响因子：
0
作者：
Lai,JH;Marsilje,TH;Choi,S;Nair,SA;Hangauer,DG
通讯作者：
Hangauer,DG

Tetrapeptide tyrosine kinase inhibitors. Enantioselective synthesis of p-hydroxymethyl-L-phenylalanine, incorporation into a tetrapeptide, and subsequent elaboration into p-(R,S-hydroxyphosphonomethyl)-L-phenylalanine.