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

• 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
• 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

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）：Apurinic/ ap嘧啶DNA修复内切酶-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；因此简称APE/Ref-1。近年来，APE/Ref-1作为一个有吸引力的可药物靶点，被广泛用于开发治疗人类恶性肿瘤的有效抑制剂；但据我们所知，只有有限的成功报道。鉴于APE/Ref-1的氧化还原功能在活性氧（ROS）相关的炎症状态、癌变和恶性进展中起着关键作用，本研究的重点是利用基于结构的方法开发APE/Ref-1的新型氧化还原抑制剂，并对我们的先导化合物进行化学优化。在我们的筛选中确定的候选化合物将进一步在体外和体内进行生物评价。我们希望开发1-2个候选APE/Ref-1氧化还原抑制剂，这些抑制剂具有良好的临床前活性，并准备转化为临床治疗和可能的治疗性预防试验