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：
10614423
负责人：
RICHARD B SILVERMAN
金额：
$ 36.02万
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/10614423
关键词：
Acute Amino Acids Ammonia Animal Model Animals Apoptosis Arginine Autophagocytosis Binding Biological Markers Cancer Etiology Cancer cell line Cell Aging Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Line Cell Proliferation Cell Proliferation Regulation Cessation of life Chemotherapy and/or radiation Chemotherapy-Oncologic Procedure Colon Carcinoma Complex Computer Models Crystallography Dialysis procedure Drug Kinetics Electrodes Encephalopathies Enzymes Fluoride Ion Genes Glioblastoma Glutamates Glutamine Goals Growth Growth Inhibitors Human Hydroxyproline Implant In Vitro Intoxication Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Mass Spectrum Analysis Measurement Measures Metabolism Modeling Modification 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 cancer therapy carboxylate carboxylation chemotherapy comparative design enzyme pathway enzyme structure improved in vivo inhibitor men molecular dynamics molecular modeling mouse model novel therapeutic intervention overexpression patient derived xenograft model pyrroline pyrroline 5 carboxylate reductase screening side effect 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.

项目摘要/摘要最近，发现酶鸟氨酸氨基转移酶（OAT）过表达肝细胞癌（HCC），肝脏最常见的主要原发性恶性肿瘤和第二个主要原因全球男性（女性第六名）与癌症有关的死亡。已知抑制的分子相对较少燕麦的活性以及已有报道的燕麦的活动集中于他们增加浓度的能力鸟氨酸是急性氨毒性和肝发育性脑病的潜在治疗方法。这该建议的目的是根据人燕麦的已知晶体结构使用计算机建模以及其他与我们以前活跃的灭活剂约束的依赖PLP的酶，以帮助设计反对其他相关酶有选择性的燕麦灭活剂，以降低副作用的潜力脱离目标抑制。对我们早期化合物的修改将改善效力和药代动力学特性。那些选择性灭活燕麦的化合物的机制将是调查。我们的合作者博士将获得与燕麦束缚的灭活剂的X射线晶体结构。达利·刘（Dali Liu），协助进一步的结构修改。具有有效和选择性灭活因子的化合物 Wenan Qiang博士将对几种癌细胞系进行测试，也发现燕麦过表达燕麦和用最有效的化合物进行PDX研究。他还将证实化合物抑制 HCC的生物标志物的α-毒素分泌，燕麦是靶标。目标是确定一个或更多的化合物，这些化合物是抑制HCC生长的燕麦的选择性抑制剂/灭活剂在动物中过表达燕麦的癌症。这些化合物将是HCC的第一类治疗方法对标准癌症化疗和放射疗法高度抗药性的癌症以及预后对于恢复也很差，以及其他表达燕麦的癌症。