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：
9335285
负责人：
SUN YANG
金额：
$ 11.31万
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/9335285
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 Human In Vitro Inflammatory JUN gene Lead Legal patent Life Malignant - descriptor Malignant Neoplasms Measurement Measures Mediating Mentors Mentorship Methods Molecular Monitor NF-kappa B Neoplasm Metastasis Nuclear Oxidation-Reduction Patients Pharmacologic Substance Pharmacology 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 Xenograft procedure base carcinogenesis career career development chemotherapy computer program design drug candidate drug development drug discovery endonuclease experience high throughput screening in vitro activity in vivo inhibitor/antagonist melanoma mortality mouse model novel novel therapeutics overexpression pre-clinical public health relevance repair enzyme research clinical testing screening small molecule success three-dimensional modeling 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（申请人提供）：脱嘌呤/脱嘧啶DNA修复核酸内切酶-1（APE-1）是一种重要的DNA切除修复酶，它还具有氧化还原调节功能，称为氧化还原因子-1（Ref-1），并激活许多核转录因子；因此缩写为 APE/Ref-1。以APE/Ref-1作为一个有吸引力的药物靶标，近年来人们致力于开发有效的抑制剂来治疗人类恶性肿瘤；但据我们所知，只报道了有限的成功。鉴于 APE/Ref-1 的氧化还原功能在活性氧中起着关键作用，该提案的重点是利用基于结构的方法对我们的先导化合物进行化学优化，开发新型 APE/Ref-1 氧化还原抑制剂（ROS）相关的炎症状态、癌发生和恶性进展。我们筛选中确定的候选化合物将进一步进行体外和体内生物评价。我们期望开发 1-2 种候选 APE/Ref-1 氧化还原抑制剂，这些抑制剂表现出有希望的临床前活性，并准备好转化为临床治疗和可能的治疗性预防试验未来5年内。为了实现这一科学和转化目标，职业发展补助金将为我提供必要的资金、指导和经验，使我成为一名独立的临床科学家，在一个非常有利于促进和维持年轻研究人员成功的环境中工作。这笔职业发展补助金将为我提供相关综合培训和发展必要专业知识的机会，以组建和领导药物开发领域的多专业团队。