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.
Sasaki, Atsuo Title: Chemical probes that modulate a stress pathway phosphatidylinositol 5-phosphate 4-kinase activity We have discovered that PI5P4K, phosphatidylinositol-5-phosphate 4-kinase (Type II PIPK), regulates insulin signaling and tumor cell growth. Our data indicates that targeting PI5P4K activity would provide a novel approach to promote synthetic lethality in certain type of cancers. Therefore in this proposal, we aim to identify and optimize specific modulators of human PI5P4K using a quantitative high-throughput screening approach against ~400,000 small molecules. We will test the impact and specificity of these PI5P4K inhibitors on tumor cell growth. PUBLIC HEALTH RELEVANCE: PI5P4K is essential for cell proliferation of certain types of cancers. The goal of this project is to discover specific small molecule modulators of PI5P4K, subsequently leading to the development of novel cancer drugs. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
|Sumita, Kazutaka; Lo, Yu-Hua; Takeuchi, Koh et al. (2016) The Lipid Kinase PI5P4K? Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis. Mol Cell 61:187-98|
|Takeuchi, Koh; Senda, Miki; Lo, Yu-Hua et al. (2016) Structural reverse genetics study of the PI5P4K?-nucleotide complexes reveals the presence of the GTP bioenergetic system in mammalian cells. FEBS J 283:3556-3562|