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

• 批准号: 10390338
• 负责人: RICHARD B SILVERMAN
• 金额: $ 35.8万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 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/10390338
• 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; Malignant Neoplasms; Malignant neoplasm of liver; 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; 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

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/摘要 最近，发现酶鸟氨酸氨基转移酶（OAT）在大肠杆菌中过表达。 肝细胞癌（HCC）是肝脏最常见的原发性恶性肿瘤，也是第二大病因 全球男性癌症相关死亡率（女性第6位）。相对来说， OAT的活性以及已报道的那些活性集中在它们增加 鸟氨酸作为急性氨中毒和肝源性脑病的潜在治疗。的 该建议的目的是基于已知的人类OAT晶体结构，使用计算机建模 和其他PLP依赖性酶与我们以前的活性灭活剂结合，以帮助设计新的 OAT的灭活剂对其他相关酶具有选择性，以降低 脱靶抑制我们将对早期的化合物进行修改，以提高效力， 药代动力学特性这些化合物选择性地抑制OAT的机制将是 研究了与OAT结合的灭活剂的X射线晶体结构将由我们的合作者， 刘大力先生协助进行进一步结构修改。是有效的和选择性的灭活剂的化合物， Wenan Qiang博士将针对几种也发现过表达OAT的癌细胞系测试OAT， 使用最有效的化合物进行PDX研究。他还将证实，化合物抑制 甲胎蛋白分泌，HCC的生物标志物，OAT是靶点。目标是确定一个或 作为抑制HCC生长的OAT的选择性抑制剂/灭活剂的更多化合物，以及其他 在动物中过度表达OAT的癌症。这些化合物将成为HCC的一流治疗方法， 对标准癌症化疗和放射治疗高度耐药的癌症，以及预后 对于恢复是非常差的，以及其他OAT表达癌症。