Isolation of Inhibitors of Her-Kinase Expression (RMI)

Her 激酶表达抑制剂 (RMI) 的分离

• 批准号: 7058517
• 负责人: GABRIELA CHIOSIS
• 金额: $ 0.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058517
• 关键词: aggression; antineoplastics; bioassay; drug discovery /isolation; drug screening /evaluation; enzyme activity; enzyme induction /repression; high throughput technology; method development; neoplasm /cancer; oncoproteins; protein degradation; protein tyrosine kinase; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Human, cancers frequently express high levels of transmembrane tyrosine kinases of the Her family. Overexpression of at least one of these, the Her2 receptor, has been associated with a more aggressive behavior. Several therapeutic strategies targeting the receptor are now in various stages of clinical development. Most of the known agents block the activation or inhibit the activity of Her2; however, a more significant therapeutic outcome may result from degrading this oncoprotein. We propose here a cell-based assay that may be used to conduct high-throughput screens (HTS) to isolate Her2 kinase expression inhibitors. The compounds identified from these efforts will represent important leads that will serve as the starting point to obtain drugs that modulate Her2 expression. These drugs could, in principle, be used to treat patients with advanced cancers driven by Her2-overexpression/oversignalling. Given the importance of Her-kinases in human disease, the time is ripe to design and perform a large-scale screening regimen to identify Her-kinase expression modulators. To our knowledge, this has not been accomplished, and we believe that we are uniquely positioned to initiate this goal.

描述（由申请人提供）：人类癌症经常表达高水平的 Her 家族跨膜酪氨酸激酶。其中至少一种（Her2 受体）的过度表达与更具攻击性的行为有关。几种针对该受体的治疗策略目前正处于临床开发的不同阶段。大多数已知药物可阻断 Her2 的激活或抑制其活性；然而，降解这种癌蛋白可能会产生更重要的治疗结果。我们在这里提出了一种基于细胞的测定法，可用于进行高通量筛选（HTS）以分离 Her2 激酶表达抑制剂。从这些工作中鉴定出的化合物将代表重要的线索，将作为获得调节 Her2 表达的药物的起点。原则上，这些药物可用于治疗由 Her2 过度表达/过度信号传导驱动的晚期癌症患者。鉴于 Her 激酶在人类疾病中的重要性，设计和实施大规模筛选方案来鉴定 Her 激酶表达调节剂的时机已经成熟。据我们所知，这一目标尚未实现，但我们相信我们具有独特的优势来实现这一目标。