权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Antifolate activators of AMP-dependent protein kinase

AMP 依赖性蛋白激酶的抗叶酸激活剂

基本信息

批准号：
8403807
负责人：
RICHARD G MORAN
金额：
$ 27.26万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-02 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403807
关键词：
5&apos -AMP-activated protein kinase Active Sites Address Affect Alleles Anabolism Binding Biochemical Genetics Cancer Etiology Cell Line Cells Cellular biology Characteristics Collection Colon Carcinoma Drug Design Drug usage Effectiveness Employee Strikes Energy Metabolism Enzymatic Biochemistry Enzyme Kinetics Enzymes Event FDA approved Feedback Folate Folic Acid Antagonists Genes Genetic Genotype Goals Growth Human Hydroxymethyltransferases Hyperactive behavior In Vitro Kinetics Lead Learning Leukemic Cell Malignant Epithelial Cell Malignant Neoplasms Mesothelioma Metabolic Metabolism Methods Modification Molecular Genetics Mutation Non-Small-Cell Lung Carcinoma Nuclear Oncogene Activation Oncogenes PTEN gene Pathway interactions Pemetrexed Pharmaceutical Preparations Protein Kinase Protein Kinase Interaction Proteins Proto-Oncogene Proteins c-akt Purine Antagonist Purines Pyrimidines Reaction Ribonucleotides Role STK11 gene Signal Transduction Structure TSC1/2 gene Therapeutic Therapeutic Agents Thymidylate Synthase Thymidylate Synthase Inhibitor Tumor Suppressor Genes analog antitumor agent base cancer cell conditioning cytotoxicity design drug development folic acid metabolism genetic profiling human FRAP1 protein in vivo inhibitor/antagonist lung Carcinoma mTOR inhibition neoplastic cell polyglutamates purine research study tool tumor

项目摘要

Summary The majority of human cancers have lost the function of tumor suppressor genes (LKB1, PTEN, TSC1/2) controlling energy metabolism on the Akt-mTOR pathway or have hyperactivity of oncogenes (PI3kinase, Akt) on this same pathway. We have found that drugs that inhibit the second folate-dependent enzyme on the de novo purine biosynthesis pathway cause the accumulation of the substrate for that reaction, ZMP, and that this endogenously synthesized ZMP activates AMP-dependent protein kinase. Compounds that activate AMP kinase hava potential as antitumor agents since this enzyme acts as a key regulator of TORC1 on this pathway, restoring control in tumor cells with these genetic changes. This project proposes to study inhibitors of purine synthesis at the biochemical and molecular genetic levels to determine the mechanism of these effects and the utility of these inhibitors specifically to treat cancers that have genetic defects in the PI3kinase-mTOR pathway. The enzymology and cell biology of the lead compounds would be studied, and more potent inhibitors of the AICART formyltransferase reaction would be designed as targeted therapeutic agents

总结