Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases

用于靶向氧化还原敏感激酶的亲核抑制剂

基本信息

批准号：
8631369
负责人：
Kate Suzanne Carroll
金额：
$ 39.22万
依托单位：
SCRIPPS FLORIDA
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：
2013-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631369
关键词：
6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-one Achievement Active Sites Advanced Malignant Neoplasm Amino Acids Antineoplastic Agents Binding Sites Biochemical Biochemistry Biological Assay Biological Models Cancer cell line Case Study Cellular Assay Chemicals Chemistry Clinical Trials Cysteine Development Disease Drug Kinetics Drug Targeting Effectiveness Electrons Environment Epidermal Growth Factor Receptor Evaluation Exposure to Foundations Future Gefitinib Glutathione Goals Human Human Development Hydrogen Peroxide In Vitro Intervention Investigation Lead Libraries Light Lysine Malignant Neoplasms Modeling Modification Molecular Oxidation-Reduction Oxidative Stress Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Physiological Play Protein Kinase Protein Tyrosine Kinase Proteins Regulation Resistance Role Signal Pathway Site-Directed Mutagenesis Structure Sulfenic Acids Sulfur Testing Therapeutic Human Experimentation Tissue Sample Toxic effect Treatment Efficacy Tumor Tissue Work adduct anti-cancer therapeutic base cancer cell design improved in vivo inhibitor/antagonist insight kinase inhibitor lapatinib novel novel diagnostics novel strategies oxidation pre-clinical prevent prototype public health relevance receptor scaffold small molecule standard of care tool tumor progression tumor xenograft

项目摘要

Abstract Kinase inhibition has emerged as the preeminent point of intervention for developing novel anti-cancer therapeutics and research tool compounds to dissect signaling pathways. In this proposal, we focus on redox- sensitive kinases and the development of inhibitors that target the oxidized form of these proteins, which are prevalent in many human cancers. In Aim 1, we identify chemical warheads that target cysteine oxidation species. In Aim 2, we develop molecules that target oxidized tyrosine kinases and evaluate their effectiveness in vitro and cancer cell-based assays. In Aim 3, we evaluate the therapeutic efficacy of new kinase inhibitors. Inhibitors identified in this study will serve as vital tools for dissecting mechanistic details of kinase redox regulation and the relationship between oxidative stress/aberrant kinase activity in cancer. Furthermore, these collective aims will create a foundation for the development of an entirely new class of anti-cancer drugs.

抽象的激酶抑制已成为发展新型抗癌的最重要的干预措施治疗和研究工具化合物剖析信号通路。在此提案中，我们专注于氧化还原敏感激酶和靶向这些蛋白质氧化形式的抑制剂的发展，这些蛋白质是在许多人类癌症中普遍存在。在AIM 1中，我们确定靶向半胱氨酸氧化的化学弹头物种。在AIM 2中，我们开发了靶向氧化酪氨酸激酶并评估其有效性的分子体外和基于癌细胞的测定。在AIM 3中，我们评估了新的激酶抑制剂的治疗功效。在本研究中确定的抑制剂将是剖析激酶氧化还原机械细节的重要工具调节和癌症中氧化应激/异常激酶活性之间的关系。此外，这些集体目标将为开发全新的抗癌药物创造基础。