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: 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
• 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

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，鸟氨酸氨基转移酶(OAT)在卵巢癌中过表达。 肝细胞癌是肝脏最常见的原发恶性肿瘤，居第二位 在全球范围内，与癌症相关的死亡在男性(女性中排名第6)中的比例最高。已知的抑制分子相对较少 燕麦的活动，以及那些已被报告的活动，侧重于它们增加 鸟氨酸作为治疗急性氨中毒和肝源性脑病的潜在药物。这个 这项建议的目的是使用计算机模拟，基于已知的人类燕麦的晶体结构 和其他依赖PLP的酶与我们先前活性的灭活剂结合，以帮助设计新的 燕麦的灭活剂，对其他相关酶具有选择性，以降低潜在的副作用 偏离目标的抑制。我们将对以前的化合物进行修改，以提高效力和 药代动力学特性。这些化合物选择性地灭活燕麦的机理将是 调查过了。与OAT结合的钝化剂的X射线晶体结构将由我们的合作者Dr。 刘大理，协助进一步的结构调整。是有效和选择性的灭活剂的化合物 强文安博士将测试燕麦对几种癌细胞株的作用，这些癌细胞也被发现过度表达燕麦和 使用最有效的化合物进行PDX研究。他还将证实这些化合物能抑制 分泌甲胎蛋白，这是肝细胞癌的生物标志物，而燕麦是靶标。目标是确定一个或多个 更多的化合物是燕麦的选择性抑制剂/失活剂，可以抑制肝癌的生长，以及其他 在动物体内过度表达燕麦片的癌症。这些化合物将是治疗肝癌的一流药物， 对标准癌症化疗和放射治疗高度耐药的癌症，以及预后 对于恢复非常差的癌症，以及其他表达燕麦片的癌症。