Inhibitors of Dynamin as Novel Anti-Cancer Therapeutics

Dynamin 抑制剂作为新型抗癌疗法

• 批准号: 6700914
• 负责人: Sandra L. Schmid
• 金额: $ 16.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-12 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700914
• 关键词: affinity chromatography; antineoplastics; apoptosis; biological signal transduction; biotherapeutic agent; cell proliferation; combinatorial chemistry; drug discovery /isolation; dynamin; endocytosis; enzyme activity; enzyme inhibitors; guanine nucleotide binding protein; guanosinetriphosphatases; high throughput technology; mass spectrometry; neoplasm /cancer chemotherapy; p53 gene /protein

DESCRIPTION (provided by applicant): As realized by this RFA, there is a need to identify novel molecular targets for cancer drug discovery. Among these will be molecules that directly regulate the intrinsic apoptotic pathway. We recently discovered that the large GTPase dynamin-2 (dyn2) signals through p53 to trigger apoptosis, specifically in rapidly dividing cells. As little as five-fold overexpression of endogenous wild-type dyn2 will activate p53-dependent apoptosis and this is absolutely dependent on GTP binding. A mutation defective in dynamin's intrinsic GAP activity is even more potent. Thus, compounds that inhibit dynamin's GTPase activity or its intrinsic GAP may be effective proapoptotic, anti-cancer drugs. To identify these compounds we have developed a simple and robust high-throughput assay for dynamin GTPase activity and established a collaboration with Barry Sharpless, a leading chemist who has pioneered a new azido-based method of "click chemistry" that facilitates the generation of complex libraries of related compounds, allows for rapid modular SAR of identified leads and most importantly and uniquely allows the assembly of functional moieties to be selected for on the surface of the target molecule to generate customized, high-affinity, high-specificity inhibitors. We propose the following Specific Aims that will allow us to apply click chemistry to identify potential anti-cancer drugs targeted against the regulatory GTPase, dynamin. 1. To identify, characterize and optimize high affinity, high specificity compounds that inhibit dynamin's basal GTPase activity. 2. To identify, characterize and optimize high affinity, high specificity compounds that selectively inhibit dynamin's assembly-stimulated GTPase activity. 3. To apply click chemistry for in situ selection of very high affinity, very high specificity inhibitors on dynamin, itself.

描述（由申请人提供）：如该RFA所实现的那样，有必要确定新的分子靶标的癌症药物发现。其中将是直接调节固有凋亡途径的分子。我们最近发现，大型GTPase Dynamin-2（Dyn2）通过p53信号触发凋亡，特别是在迅速分裂的细胞中。内源性野生型Dyn2的过表达仅五倍，将激活p53依赖性凋亡，这绝对取决于GTP结合。 Dynamin内在间隙活性中有缺陷的突变更有效。因此，抑制Dynamin的GTPase活性或其内在间隙的化合物可能是有效的促凋亡，抗癌药物。为了识别这些化合物，我们为动态GTPase活性开发了一种简单且可靠的高通量测定法，并与Barry Sharpless建立了合作，Barry Sharpless是一位领先的化学家Barry Sharpless，他开创了一种新的基于Azido的“点击化学方法”的方法，该方法促进了相关化合物的快速销售，并促进了良好的范围，并允许逐步构成Modiqual sar的快速范围，并不是在启用MOSULAL SARIQUES，并不是启用Modular sar sar的良好型号。目标分子的表面产生定制的高亲和力，高特异性抑制剂。我们提出以下特定目标，使我们能够应用点击化学以识别针对调节性GTPase dynamin的潜在抗癌药物。 1。识别，表征和优化高亲和力，抑制Dynamin基础GTPase活性的高特异性化合物。 2。为了识别，表征和优化高亲和力，高特异性化合物有选择地抑制Dynamin的组装刺激的GTPase活性。 3。要应用点击化学，以原位选择非常高的亲和力，对Dynamin本身的非常高的特异性抑制剂。