Chemical Probes That Modulate Phosphatidylinositol-5-Phosphate 4-Kinase Activity

调节磷脂酰肌醇 5 磷酸 4 激酶活性的化学探针

基本信息

批准号：
8403186
负责人：
Atsuo Sasaki
金额：
$ 3.83万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403186
关键词：
Affect Antineoplastic Agents Biological Assay Breast Cancer Model Cancer Model Cell Proliferation Cells Chemicals Data Data Analyses Development Embryo Family Fibroblasts Firefly Luciferases Goals Grant Human Knockout Mice Letters Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolism Methods Modeling Mus Nature PIP5K2A gene Pathway interactions Phosphotransferases Principal Investigator Production Promega Property Proto-Oncogene Proteins c-akt Radiolabeled Regulation Series Signal Transduction Specificity Stress Structure Structure-Activity Relationship Testing Titrations analog base cancer cell cancer type cell growth high throughput screening improved in vivo inhibitor/antagonist insulin signaling mouse model neoplastic cell novel novel strategies phosphatidylinositol 3-phosphate phosphatidylinositol 4-phosphate phosphatidylinositol 5-phosphate programs public health relevance radiotracer response screening small molecule tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): This proposal aims to identify and optimize specific modulators of human PI5P4K, phosphatidylinositol- 5-phosphate 4-kinase (Type II PIPK), a family of kinases that regulate AKT signaling and tumor cell growth. The following specific aims will be pursued: (1) to identify inhibitors of human PI5P4K using a quantitative high-throughput screening approach against the MLSMR containing ~400,000 small molecules. (2) To validate the potency of the identified compounds in a panel of secondary assays, which consist of selectivity assays to identify those compounds that do not affect PI4P5K, phosphatidylinositol- 4-phosphate 5-kinase (Type I PIPK), and PI3P5K, the phosphatidylinositol-3-phosphate 5-kinase (Type III PIPK /Fab1/PIKfyve). We will test the impact and specificity of these PI5P4K probes on cellular PI5P accumulation and cell proliferation using PI5P4K knockout mouse embryonic fibroblasts (MEFs) and knockdown cells as controls. (3) Beyond the granting term for this proposal, to examine the most potent PI5P4K probes for their ability to decrease tumor growth in mouse models of cancer.

描述（由申请人提供）：该提案旨在识别和优化人类PI5P4K，磷脂酰肌醇-5-磷酸4-激酶（II型PIPK）的特定调节剂（II型PIPK），这是一个调节AKT信号传导和肿瘤细胞生长的激酶家族。将采用以下特定目标：（1）使用含有约400,000个小分子的MLSMR进行定量的高通量筛选方法鉴定人PI5P4K的抑制剂。 (2) To validate the potency of the identified compounds in a panel of secondary assays, which consist of selectivity assays to identify those compounds that do not affect PI4P5K, phosphatidylinositol- 4-phosphate 5-kinase (Type I PIPK), and PI3P5K, the phosphatidylinositol-3-phosphate 5-kinase (Type III PIPK /fab1 /pikfyve）。我们将使用PI5P4K基因敲除小鼠胚胎成纤维细胞（MEFS）和敲除细胞作为对照来测试这些PI5P4K探针对细胞PI5P积累和细胞增殖的影响和特异性。（3）超出该提案的授权项，以检查最有效的PI5P4K探针，以降低癌症小鼠模型中肿瘤生长的能力。