The Development of Novel Mechanistically-based APE/Ref-1 Redox Inhibitors

新型基于机理的 APE/Ref-1 氧化还原抑制剂的开发

基本信息

批准号：
8907968
负责人：
SUN YANG
金额：
$ 11.45万
依托单位：
CHAPMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8907968
关键词：
Abbreviations Binding Biological Assay Bioluminescence Cell Culture Techniques Chemicals Clinical Pharmacists Clinical Pharmacology Clinical Treatment Complex DNA DNA Repair Endonuclease Development Docking EMSA Electrophoretic Mobility Shift Assay Environment Evaluation Excision Repair Exhibits Funding Genetic Transcription Goals Grant Health Human In Vitro Inflammatory JUN gene Lead Legal patent Life Malignant - descriptor Malignant Neoplasms Measurement Measures Mediating Mentors Mentorship Methods Modeling Molecular Monitor NF-kappa B Neoplasm Metastasis Nuclear Oxidation-Reduction Patients Pharmacologic Substance Play Prevention trial Process Property Proteins Reactive Oxygen Species Regulation Reporter Reporting Research Research Personnel Resistance Role Scientist Signal Transduction Structure Supervision Testing Therapeutic Training Transcription Factor AP-1 Translating Translations Work Xenograft procedure antitumor effect base carcinogenesis career career development chemotherapy computer program design drug candidate drug development drug discovery endonuclease experience high throughput screening human APEX1 protein in vitro activity in vivo inhibitor/antagonist melanoma mortality mouse model novel overexpression pre-clinical repair enzyme research clinical testing screening small molecule success three dimensional structure tomography transcription factor tumor tumor growth tumor progression virtual

项目摘要

DESCRIPTION (provided by applicant): Apurinic/apyrimidinic DNA repair endonuclease-1 (APE-1) is an important DNA excision repair enzyme, which also has a redox regulatory function known as Redox Factor-1 (Ref-1) and activates many nuclear transcription factors; hence the abbreviation APE/Ref-1. Taking APE/Ref-1 as an attractive druggable target, many efforts have been devoted in recent years to develop potent inhibitors for the treatment of human malignancies; but to the best of our knowledge, only limited success has been reported. This proposal centers on the development of novel redox inhibitors of APE/Ref-1 utilizing structure- based approaches with chemical optimization of our lead compounds, given the fact that the redox function of APE/Ref-1 plays a critical role in reactive oxygen species (ROS)-associated inflammatory states, carcinogenesis and malignant progression. Candidate compounds identified in our screening will be advanced to further bio-evaluation both in vitro and in vivo. W expect to develop 1-2 candidate APE/Ref-1 redox inhibitors that exhibit promising preclinical activity and ready for translation to clinical treatment and possibly therapeutic prevention trials within the next 5 years. In order to achieve this scientific and translational goal, a career development grant will provide me with the necessary funding, mentorship, and experience to become an independent clinician scientist working in an environment that is highly conductive to promoting and sustaining success of young investigators. This career development grant will provide me the opportunity for relevant comprehensive training and development of the requisite expertise to assemble and lead a multi-expertise team in drug development.

描述（由申请人提供）：肾上腺素/阿哌丁素DNA修复核酸酶-1（APE-1）是一种重要的DNA切除修复酶，它也具有称为氧化还原因子1（Ref-1）的氧化还原调节函数，并激活许多核核转录因子；因此，缩写猿/ref-1。以APE/Ref-1为有吸引力的毒品目标，近年来已经致力于为治疗人类恶性肿瘤的有效抑制剂提供许多努力。但是据我们所知，只有有限的成功。该提案集中于新型氧化还原抑制剂的发展，鉴于APE/Ref-1的氧化还原功能在活性氧中起着至关重要的作用，利用基于结构的方法利用基于结构的方法利用了基于结构的方法。（ROS）相关炎症状态，致癌和恶性进展。在我们的筛查中确定的候选化合物将在体外和体内进一步进一步进行生物评估。 W期望开发1-2个候选猿/Ref-1氧化还原抑制剂，该抑制剂表现出有希望的临床前活动，并准备转化为临床治疗，并可能进行治疗预防试验在接下来的5年内。为了实现这一科学和翻译目标，职业发展赠款将为我提供必要的资金，指导和经验，以成为一名独立的临床医生，在一个高度有效的环境中工作，以促进和维持年轻研究人员的成功。这项职业发展赠款将为我提供相关的全面培训和开发必要专业知识的机会，以组装和领导一支多型药物开发团队。