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：
9187426
负责人：
Kate Suzanne Carroll
金额：
$ 39.84万
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/9187426
关键词：
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 Hydrogen Peroxide In Vitro Intervention Investigation Lead Libraries Light Lysine Malignant Neoplasms Modeling Modification Molecular Oxidation-Reduction Oxidative Stress Oxides Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Physiological Play Protein Deregulation Protein Kinase Protein Tyrosine Kinase Proteins Regulation Resistance Role Signal Pathway Site-Directed Mutagenesis Structure Sulfenic Acids Sulfur Sulfuric Acids Testing Therapeutic Therapeutic Human Experimentation Tissue Sample Toxic effect Treatment Efficacy Tumor Tissue Work adduct anti-cancer therapeutic base cancer cell comparative efficacy counterscreen design improved in vivo inhibitor/antagonist insight kinase inhibitor lapatinib novel novel diagnostics novel strategies oxidation preclinical development prevent prototype public health relevance receptor scaffold small molecule standard of care tool tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): 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 fo 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.

描述（由申请人提供）：激酶抑制已成为开发新型抗癌治疗和研究工具化合物以剖析信号传导途径的重要干预点。在此提案中，我们专注于氧化还原敏感的激酶以及靶向这些蛋白质氧化形式的抑制剂的发展，这些蛋白质在许多人类癌中都普遍存在。在AIM 1中，我们确定靶向半胱氨酸氧化物种的化学弹头。在AIM 2中，我们开发了靶向氧化酪氨酸激酶并评估其在基于癌细胞和癌细胞基于癌细胞的测定的有效性的分子。在AIM 3中，我们评估了新的激酶抑制剂的治疗功效。在这项研究中确定的抑制剂将作为重要工具，可以解剖激酶氧化还原调节的机理细节以及癌症中氧化应激/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。