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

奥古斯塔的创始实验室使用了尖端的基因技术和shRNA筛选方法，发现了ROS受体酪氨酸激酶作为癌症生存基因。来自其他实验室的研究基于遗传学发现、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(如胶质母细胞瘤，IV级星形细胞瘤)的发展和/或进展之间的明确联系。综上所述，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基础。这项建议的总体目标是开发抑制ROS受体酪氨酸激酶活性的小分子，作为人类多形性胶质母细胞瘤(GBM)的主要适应症。这项建议的具体目标是利用标准的药物化学实践进一步开发原型化合物，以产生更有效的ROS抑制剂，通过两种方法进行判断：1)体外抑制酶活性；2)选择性抑制表达异常ROS的胶质母细胞瘤细胞系与正常胶质细胞相比。如果满足这些标准，那么我们已经验证了一种结构优化和具有生物活性的分子(即先导化合物)，该分子可以推进到第二阶段计划。

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.