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Identifying the Molecular Targets of Novel Cytotoxic Agents

识别新型细胞毒剂的分子靶点

基本信息

批准号：
7315650
负责人：
JEF KAREL DE BRABANDER
金额：
$ 85.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7315650
关键词：
6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene Affinity Chromatography Animals Antimitotic Agents Antineoplastic Agents Binding Biochemical Biochemical Genetics Biochemistry Biological Biological Factors Caenorhabditis elegans Cancer Cell Growth Cells Cellular biology Chemicals Chemistry Class Clinical Collaborations Complex Cytotoxic agent Cytotoxin DMA-methyltransferase DNA Methyltransferase DNA Modification Methylases Development Developmental Therapeutics Program Drug resistance Enzymes Gene Mutation Genes Genetic Genetic Screening Goals HTI-286 Histone Deacetylase Inhibitor Human Immunosuppressive Agents In Vitro Laboratories Lead Libraries Light Malignant Neoplasms Mammalian Cell Marines Missense Mutation Molecular Molecular Target Multi-Drug Resistance Mutation Nematoda Oceans Palau Palau&apos amine Pharmaceutical Preparations Pharmacology Phase Proteins Public Health Purpose Radiolabeled Reagent Reporting Research Research Personnel Resistance Role Screening procedure Signal Pathway Sirolimus Structure Toxin Trapoxin Tubulin Variant analog anticancer research base cell growth cyclopamine cytotoxicity drug sensitivity gain of function hemiasterlin high throughput screening in vivo inhibitor/antagonist interest killings loss of function mRNA Differential Displays mutant novel novel therapeutics positional cloning programs prohibitin radiotracer research study resistance mechanism scaffold smoothened signaling pathway

项目摘要

Compounds that have evolved naturally to inhibit cell growth have proven invaluable in cancer research and therapy. They often exert their effects potently andspecifically - making them useful probes of signaling pathways. Recent examples include the histone deacetylase inhibitor trapoxin, the immunosuppressant rapamycin, and the Sonic Hedgehog signaling inhibitor cyclopamine. The goal of this project is to determine the targets and mode-of-actionfor several newnatural products - ones we believe have similar potential to drive new cell biology research relevant to human cancer. The compounds also represent lead structures for the development of novel therapeutics. A multi-pronged approach combining classical genetics, reverse genetics, chemistry, cell biology, and biochemistry will be used for these purposes. Specifically, we propose to continue genetic studies of a new mechanism of drug resistance uncovered with the anti-mitotiic hemiasterlin. This is relevant in light of the advanced clinical status of HTI-286, a hemiasterlin derivative currently in Phase II human trials. We also propose to identify the target of the natural product psymberin, which was recently reported to display differential cytotoxicity in the NCI Developmental Therapeutics in Vitro Screening Program.We have achieved a practical total synthesis of this natural product, which allows access to synthetic variants for mode-of-action studies. We have shown psymberin is highly toxic to the nematode C elegans-a basis for genetic screens to identify resistant mutants. Palau'amlne is a rare natural product from the ocean having immunosuppressive and antiproliferative activities. Its synthesis is near completion and similar approaches (genetic and biochemical) will be applied to dissect its mode-of- action. Finally, we will pursue the mode-of-action of the cytotoxin halomon, a molecule shown to inhibit the DMA methyltransferase I enzyme. Relevance to public health: A large fraction of FDAapproved anticancer drugs and many more in development are based upon natural product leads. This research will investigate new natural products that operate by unique mechanisms to inhibit human cancer cell growth.

自然进化的抑制细胞生长的化合物已被证明在癌症研究和