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Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer

开发新型鸟氨酸脱羧酶抑制剂预防皮肤病

基本信息

批准号：
9194388
负责人：
Zigang Dong
金额：
$ 31.64万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9194388
关键词：
Active Sites Adverse effects Affinity Allosteric Site Anabolism Animal Experiments Binding Binding Proteins Binding Sites Biological Assay Biological Models Cancer Cell Growth Chemoprevention Chinese Traditional Medicine Colon Colon Carcinoma Computational Biology Computer Simulation Crystallization DL-alpha-Difluoromethylornithine Data Databases Development Docking Dose Enzymes FDA approved Growth Human Inflammation Intraepithelial Neoplasia Modeling Mus Ornithine Decarboxylase Ornithine Decarboxylase Inhibitor Pharmaceutical Preparations Polyamines Research Personnel Risk Factors Site Skin Skin Cancer Skin Carcinogenesis Structure Study models System Technology Testing Tissues Toxic effect Tumor Promoters antibiotic G 418 cancer cell cancer type carcinogenesis cell transformation cell type colon carcinogenesis colon tumorigenesis design dimethylbenzanthracene hearing impairment in vivo inhibitor/antagonist mouse model neoplastic novel prevent public health relevance screening skin cancer prevention small molecule small molecule inhibitor supercomputer targeted agent tumor

项目摘要

DESCRIPTION (provided by applicant): Increased polyamine synthesis and inflammation are associated with intraepithelial neoplasia, which are risk factors for various types of cancer development in humans. Ornithine decarboxylase (ODC) is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated ODC activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. Difluoromethylornithine (DFMO) is an approved FDA drug that acts as an irreversible and specific ODC inhibitor, and reportedly prevents carcinogenesis, especially in the skin and colon. However, high doses of DFMO in humans are associated with various degrees of hearing loss. By using computational biology with the BlueGene/L supercomputer, we have found at least one small molecule allosteric inhibitor of ODC that is less toxic and more potent than DFMO in suppressing skin and colon carcinogenesis. In this application, we propose to use state of the art technologies to identify and test additional novel, nontoxic small molecule inhibitors of ODC. These approaches include determining binding, binding affinities, specific binding sites and resulting structural changes by computation simulation using the BlueGene/L Supercomputer and our newly acquired GPU system, and performing protein binding assays, cell transformation assays and in vivo animal experiments, including the 2-stage mouse skin carcinogenesis model and the APCmin mouse model. Through these studies, we will develop more effective agents targeting ODC with fewer side effects for the chemoprevention of skin cancer and colon cancer.

描述（由申请人提供）：多胺合成增加和炎症与上皮内瘤形成相关，上皮内瘤形成是人类各种类型癌症发展的风险因素。鸟氨酸脱羧酶（ODC）在许多癌细胞类型中高度表达，并促进生长和肿瘤形成。在致癌模型系统和肿瘤组织中升高的ODC活性表明这种酶是化学预防的有效靶点。二氟甲基鸟氨酸（DFMO）是FDA批准的药物，作为一种不可逆的特异性ODC抑制剂，据报道可预防致癌作用，特别是皮肤和结肠。然而，人体中高剂量的DFMO与不同程度的听力损失有关。通过使用计算生物学与BlueGene/L超级计算机，我们已经发现了至少一种小分子变构抑制剂的ODC，是毒性较低，更有效的比DFMO抑制皮肤和结肠癌的发生。在本申请中，我们建议使用最先进的技术来鉴定和测试ODC的其他新型无毒小分子抑制剂。这些方法包括使用BlueGene/L超级计算机和我们新获得的GPU系统通过计算模拟来确定结合、结合亲和力、特异性结合位点和所产生的结构变化，以及进行蛋白结合测定、细胞转化测定和体内动物实验，包括2阶段小鼠皮肤癌发生模型和APCmin小鼠模型。通过这些研究，我们将开发出更有效的药物靶向ODC的皮肤癌和结肠癌的化学预防，副作用少。