TAS::75 0849::TAS DEVELOPMENT OF ROS KINASE INHIBITORS - PHASE I SBIR TOPIC 255

TAS::75 0849::TAS ROS 激酶抑制剂的开发 - I 期 SBIR 主题 255

• 批准号: 8174112
• 负责人: DORRE A GRUENEBERG
• 金额: $ 20.32万
• 依托单位: AUGUSTA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174112
• 关键词: Animal Model; Astrocytoma; Biological; Biological Assay; Brain Neoplasms; Cancer cell line; Cell Line; Cytotoxic agent; Data; Development; Gene Expression; Genes; Genetic; Glioblastoma; Growth; Human; In Vitro; Laboratories; Laboratory Finding; Lead; Libraries; Link; Malignant Neoplasms; Malignant neoplasm of brain; Metabolism; Methodology; Morbidity - disease rate; Neuroglia; Normal Cell; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Phosphotransferases; Protein Kinase; Receptor Protein-Tyrosine Kinases; Relative (related person); Screening procedure; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; Tumor Cell Line; base; cytotoxicity; genetic technology; in vitro activity; inhibitor/antagonist; kinase inhibitor; mortality; programs; prototype; small hairpin RNA; small molecule

The Augusta founding laboratories have used cutting edge genetic technologies and shRNA screening methodologies to uncover the ROS receptor tyrosine kinase as a cancer survival gene. Studies from other laboratories have drawn a clear link between ROS kinase activity and the development and/or progression of astrocytic tumors such as glioblastoma, a grade IV astrocytoma, based on genetic findings, gene expression data, and animal models. Taken together, these findings validate a scientific rationale that links ROS kinase activity to glioblastoma metabolism and its associated patient morbidity and mortality. The overall objective of this proposal is to develop small molecules that inhibit the kinase activity of the ROS receptor tyrosine kinase for the primary indication of human glioblastoma multiforme (GBM). The specific objective of this proposal is to further develop prototype compounds using standard medicinal chemistry practices to generate more potent ROS inhibitors as judged by two approaches: 1) inhibition of enzymatic activity in vitro; and 2) selective growth inhibition of glioblastoma cells lines expressing aberrant ROS as compared to normal glial cells. If these criteria are satisfied, then we have validated a structurally optimized and biologically active molecule (i.e., a lead compound) that can be advanced to a Phase II program.

奥古斯塔创始实验室使用尖端遗传技术和 shRNA 筛选方法来发现 ROS 受体酪氨酸激酶作为癌症生存基因。其他实验室的研究根据遗传发现、基因表达数据和动物模型，得出了 ROS 激酶活性与星形细胞肿瘤（例如胶质母细胞瘤、IV 级星形细胞瘤）的发生和/或进展之间的明确联系。总而言之，这些发现验证了将 ROS 激酶活性与胶质母细胞瘤代谢及其相关患者发病率和死亡率联系起来的科学原理。该提案的总体目标是开发抑制 ROS 受体酪氨酸激酶激酶活性的小分子，用于人多形性胶质母细胞瘤 (GBM) 的主要适应症。该提案的具体目标是使用标准药物化学实践进一步开发原型化合物，以通过两种方法判断产生更有效的 ROS 抑制剂：1）体外酶活性抑制； 2) 与正常胶质细胞相比，表达异常 ROS 的胶质母细胞瘤细胞系的选择性生长抑制。如果满足这些标准，那么我们就验证了一种结构优化且具有生物活性的分子（即先导化合物），可以进入第二阶段计划。