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Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers

鸟氨酸转氨酶失活，治疗癌症的新方法

基本信息

批准号：
10185371
负责人：
RICHARD B SILVERMAN
金额：
$ 41.21万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10185371
关键词：
Acute Amino Acids Ammonia Animal Model Animals Apoptosis Arginine Autophagocytosis Biological Markers Cancer Etiology Cancer cell line Cell Aging Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Line Cell Proliferation Cessation of life Chemotherapy and/or radiation Chemotherapy-Oncologic Procedure Colon Carcinoma Complex Computer Models Crystallization Crystallography Dialysis procedure Drug Kinetics Electrodes Encephalopathies Enzymes Fluoride Ion Genes Glioblastoma Glutamates Glutamine Goals Growth Growth Inhibitors Human Hydroxyproline Implant In Vitro Intoxication Liver Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Measurement Measures Metabolism Modeling Modification Molecular Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organoids Ornithine Ornithine-oxo-acid aminotransferase Oxidases Oxidoreductase Pathway interactions Patients Plasma Primary carcinoma of the liver cells Prognosis Proline Proline Dehydrogenase Property Pyridoxal Phosphate Radiation therapy Recovery Reporting Resistance Roentgen Rays Structure Study models Systemic Therapy Testing Toxic effect Tumor Tissue Woman X-Ray Crystallography Xenograft procedure alpha-Fetoproteins base cancer therapy carboxylate comparative design enzyme pathway enzyme structure improved in vivo inhibitor/antagonist men molecular modeling mouse model novel strategies overexpression patient derived xenograft model pyrroline pyrroline 5 carboxylate reductase screening side effect simulation therapy resistant transcriptome sequencing triple-negative invasive breast carcinoma tumor

项目摘要

Project Summary/Abstract Recently, it was found that the enzyme ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the 2nd leading cause of cancer-related death in men (6th in women) worldwide. There are relatively few molecules known to inhibit the activity of OAT, and those that have been reported focus on their ability to increase the concentration of ornithine as a potential treatment for acute ammonia intoxications and hepatogenic encephalopathy. The objective of this proposal is to use computer modeling, based on the known crystal structures of human OAT and other PLP-dependent enzymes with our previously-active inactivators bound, to assist in the design of new inactivators of OAT that are selective against other related enzymes to lower the potential of side effects from off-target inhibition. Modifications to our earlier compounds will be made to improve on potency and pharmacokinetic properties. The mechanisms of those compounds that selectively inactivate OAT will be investigated. X-ray crystal structures of the inactivators bound to OAT will be obtained by our collaborator, Dr. Dali Liu, to assist in further structural modifications. Compounds that are potent and selective inactivators of OAT will be tested by Dr. Wenan Qiang against several cancer cell lines also found to overexpress OAT and carry out PDX studies with the most effective compounds. He also will corroborate that the compounds inhibit secretion of alpha-fetoprotein, a biomarker for HCC, and that OAT is the target. The goal is to identify one or more compounds that are selective inhibitors/inactivators of OAT that suppress the growth of HCC, and other cancers that overexpress OAT, in animals. These compounds would be first-in-class treatments for HCC, a cancer that is highly resistant to both standard cancer chemotherapy and radiation therapy, and the prognosis for recovery is very poor, as well as other OAT-expressing cancers.

项目总结/文摘