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：
8434732
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 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434732
关键词：
Active Sites Adverse effects Affinity Allosteric Site Anabolism Animal Experiments Binding Binding Sites Biological Assay Biological Models Cancer Cell Growth Chemoprevention Chinese Traditional Medicine Colon Colon Carcinoma Computational Biology Computer Simulation DL-alpha-Difluoromethylornithine Data Databases Development Docking Dose Enzymes FDA approved Human Inflammation Intraepithelial Neoplasia Lead Modeling Mus Ornithine Decarboxylase Ornithine Decarboxylase Inhibitor Pharmaceutical Preparations Polyamines Protein Binding Research Personnel Risk Factors Site Skin Skin Cancer Skin Carcinogenesis Staging 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 design dimethylbenzanthracene hearing impairment in vivo inhibitor/antagonist mouse model neoplastic novel prevent public health relevance screening simulation skin cancer prevention small molecule supercomputer tumor growth tumorigenesis

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.