Inhibitors of Kinase Activation

激酶激活抑制剂

• 批准号: 7193163
• 负责人: NATHANAEL Schiander GRAY
• 金额: $ 36.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193163
• 关键词: NIH Roadmap Initiative tag; biomedical resource; chemical registry /resource; chemical structure function; combinatorial chemistry; conformation; high throughput technology; kinase inhibitor

DESCRIPTION (provided by applicant): New inhibitors of protein kinase activity are urgently needed both as potential therapeutics for the treatment of conditions resulting from constitutively active signaling pathways and as tools for assigning function to kinases in diverse cellular contexts. While there are currently tremendous efforts to develop therapeutic kinase inhibitors by the pharmaceutical industry, the focus is predominantly on a small number of kinases that have been linked to disease. Therefore the vast majority of kinases are still not targeted by an inhibitor with a useful level of selectivity. Our long term objective is to generate narrow spectrum kinase inhibitors that will be able to inhibit all tyrosine kinases in the human genome. Recently, crystallographic analysis has revealed that a subset of kinase inhibitors bind and stabilize an inactive conformation of the kinase. We have developed and validated a pharmacophore model which will allow us to synthesize new inhibitors of kinase activation with selectivity profiles unique to all currently known kinase inhibitors. The specific aims of this grant are to deliver exploratory libraries of novel inhibitors of kinase activation to the Molecular Libraries Screening Center Network (MLSCN). In parallel, we will use a panel of cellular and enzymatic kinase assays to assign the kinase selectivity to all the new compounds that we prepare. Researchers who run assays at the NIH screening centers and find "hits" from these libraries will be able to use the annotated kinase selectivity profiles to generate immediate hypotheses regarding the kinases that maybe relevant to their particular assay of interest. We are preparing new inhibitors of proteins called kinases that are responsible for transmitting signals inside of human cells. Because many diseases are caused by kinases being turned "on" when they should not be, it maybe possible to treat these diseases by making inhibitors that can switch kinases off.

描述（由申请人提供）：迫切需要对蛋白激酶活性的新抑制剂作为治疗由组成性主动的信号通路导致的条件的潜在治疗，以及作为在各种细胞环境中为激酶分配功能的工具。尽管目前正在为制定制药行业开发治疗性激酶抑制剂的巨大努力，但重点主要放在少数与疾病有关的激酶。因此，绝大多数激酶仍然不是具有有用的选择性水平的抑制剂的靶向。我们的长期目标是产生狭窄的光谱激酶抑制剂，这些抑制剂将能够抑制人类基因组中的所有酪氨酸激酶。最近，晶体学分析表明，一部分激酶抑制剂结合并稳定激酶的非活性构象。我们已经开发了并验证了一种药效团模型，该模型将使我们能够通过所有当前已知的激酶抑制剂独有的选择性谱剂合成新的激酶激活抑制剂。该赠款的具体目的是将新型激酶激活抑制剂的探索性文库传递给分子库筛选中心网络（MLSCN）。同时，我们将使用一组细胞和酶促激酶测定面板将激酶的选择性分配给我们准备的所有新化合物。在NIH筛查中心运行测定并从这些库中找到“命中”的研究人员将能够使用带注释的激酶选择性配置文件来产生有关激酶的直接假设，这些假设可能与他们的特定检测分析有关。 我们正在准备称为激酶的蛋白质的新抑制剂，这些蛋白质是为了在人类细胞内传输信号的原因。由于许多疾病是由于激酶在不应该的情况下被“启用”引起的，因此可能通过制造可以关闭激酶的抑制剂来治疗这些疾病。