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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：
7889262
负责人：
RICHARD G MORAN
金额：
$ 29万
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/7889262
关键词：
5&apos -AMP-activated protein kinase Active Sites Address Affect Alleles Anabolism Binding Biochemical Cancer Etiology Cell Line Cells Cellular biology Characteristics Collection Colon 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 Pyrimidine Pyrimidines Reaction Ribonucleotides Role STK11 gene Signal Transduction Structure TP53 gene 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 polyglutamate polyglutamates public health relevance purine research study tool tumor

项目摘要

DESCRIPTION (provided by applicant): 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 PUBLIC HEALTH RELEVANCE: The majorities of human cancers have lost the function of tumor suppressor genes controlling energy metabolism on the Akt-mTOR pathway or have hyperactivity of cancer-causing genes on this pathway. We have found that drugs that inhibit a folate- dependent enzyme on the purine biosynthesis pathway cause the accumulation of a metabolite, ZMP, that can reactivate the AMP-dependent protein kinase that regulates this pathway, restoring control in tumor cells with these genetic changes. This project proposes to study this effect at the biochemical and molecular genetic levels and to develop potent inhibitors of this folate-dependent enzyme.

描述(申请人提供)：大多数人类癌症已经失去了控制Akt-mTOR途径能量代谢的肿瘤抑制基因(LKB1，PTEN，TSC1/2)的功能，或者在同一途径上有癌基因(PI3Kinase，Akt)的过度活跃。我们发现，抑制从头合成嘌呤生物合成途径上的第二个叶酸依赖酶的药物会导致该反应的底物ZMP的积累，并且这种内源性合成的ZMP激活AMP依赖的蛋白激酶。激活AMP激酶的化合物具有作为抗肿瘤药物的潜力，因为这种酶在这一途径上充当TORC1的关键调节因子，通过这些基因变化恢复对肿瘤细胞的控制。本项目建议在生物化学和分子遗传学水平上研究嘌呤合成的抑制剂，以确定这些作用的机制，以及这些抑制剂在治疗PI3K-mTOR途径中存在遗传缺陷的癌症方面的用途。将对先导化合物的酶学和细胞生物学进行研究，并将更有效的AICART甲酰转移酶反应抑制剂设计为靶向治疗药物公共卫生相关性：大多数人类癌症已经失去了Akt-mTOR途径上控制能量代谢的肿瘤抑制基因的功能，或者在这一途径上具有致癌基因的过度活跃。我们发现，抑制嘌呤生物合成途径上的叶酸依赖酶的药物会导致代谢产物ZMP的积累，该代谢产物可以重新激活调节这一途径的AMP依赖的蛋白激酶，从而通过这些基因变化恢复对肿瘤细胞的控制。该项目建议在生化和分子遗传水平上研究这种影响，并开发这种叶酸依赖酶的有效抑制剂。