NOVEL AUREOLIC ACID TYPE ANTITUMOR AGENTS
新型金黄色酸型抗肿瘤剂
基本信息
- 批准号:6634069
- 负责人:
- 金额:$ 24.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-06-01 至 2006-05-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION: (provided by applicant):Mithramycin (MTM) is an aureolic acid
antimicrobial and antitumor agent produced by various Streptomyces species
including S. argillaceus, which has been used, e.g., for the treatment of
testicular carcinoma. In addition, MTM is unique among anticancer agents in
that it also has been used clinically to treat cancer-caused malignant
hypercalcemia and Paget's bone disease. However, MTM's bone marrow, hepatic,
and renal toxicity limit its widespread clinical use. It is proposed to
investigate various aspects of the biosynthesis of the antitumor and
osteoclast-inhibiting agent mithramycin in order to develop analogs with
increased therapeutic indices, which also may allow the separation of the two
principal effects of MTM, (i) on cancer growth and (ii) on osteoclasts. This
will lead to novel antitumor agents and/or to therapeutics against osteoporosis
and other diseases related to bone growth disorders, and bears the potential
for a novel gene therapy concept in future. Combinatorial biosynthetic methods
will be used to provide an array of MTM analogs. For this, the biosynthetic
pathway to MTM, which is dominated by a type II polyketide synthase (PKS),
needs to be further characterized. Especially genes encoding enzymes
responsible for the late biosynthetic steps, the post-PKS tailoring enzymes,
particularly oxidoreductases and group transferases will be modified Resulting
mutant strains will help to determine the series of events within the
biosynthetic pathway and will characterize substrates and function of important
enzymes in the MTM pathway. This information will be used to design novel
compounds with specific activity-increasing functionality. In context with the
mechanism of action of MTM on osteoclasts, we want to explore whether MTM
derivatives can effect the expression of c-src, a proto-oncogene necessary for
the osteoclastic bone resorption, following the novel hypothesis that MTM and
its derivatives inhibit osteoclast bone resorption by blocking Sp 1 binding to
the promoter region of the c-src proto-oncogene.
The following three specific aims will be addressed:
(1) To further characterize the biosynthetic pathway of mithramycin and to
develop new niithramycin derivatives through selective gene inactivation and
product identification. Various group transferases and oxidoreductases will be
investigated. In addition, the mtm genes will be recombined with promising
deoxysugar biosynthesis, glycosyltransferase and oxygenase encoding genes from
other pathways to develop novel niithramycin analogs modified in their
saccharide and/or 0-atom pattern.
(2) The two oxygenases of the MTM pathway, MtmOII and MtmOIV, will be
investigated. The work on MtmOII, an early-acting oxygenase, will help to
identify the missing link between the final PKS product and
4-demethylpremithramycinone, the earliest mithramycin precursor documented to
date. Tetracyclic niithramycin analogs will be converted into their tricycic
and expected more active counterparts by overexpressing oxygenase MtmOIV in the
various glycosyltransferase deletion mutants.
(3) To assay the binding properties of MTM and its novel analogs to the GC-rich
elements in the c-myc and c-src promoters and their ability to prevent Sp 1
binding. Testing the high-affinity c-myc will follow thisand c-src binding
compounds for inhibition of gene expression in human cancer cells and for their
effects on growth and viability of normal and cancer cells. Finally, promising
c-src inhibiting analogs will be analyzed for activity against
osteoclastmediated bone resorption.
说明:(由申请人提供):米霉素(MTM)是一种金果酸
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jurgen T Rohr其他文献
Jurgen T Rohr的其他文献
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{{ truncateString('Jurgen T Rohr', 18)}}的其他基金
Exploring Post-Type II PKS Frame Modifications
探索 Post-Type II PKS 框架修改
- 批准号:
9110311 - 财政年份:2014
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
7845298 - 财政年份:2009
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
6928092 - 财政年份:2005
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
7408026 - 财政年份:2005
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
7056070 - 财政年份:2005
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
7228414 - 财政年份:2005
- 资助金额:
$ 24.39万 - 项目类别:
BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS
安古环素抗肿瘤药物的生物合成关键步骤
- 批准号:
7584055 - 财政年份:2005
- 资助金额:
$ 24.39万 - 项目类别:
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