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Abstract
Grant Number: 1R43CA099434-01 PI Name: CHAKRAVARTY, LEENA PI Email: leenac@echelon-inc.com PI Title: Project Title: Discovery of Antagonists of Phosphoinositide Signaling Abstract: DESCRIPTION (provided by applicant): Phosphoinositides are key lipid second messengers in many cellular signaling processes. In particular, the activity of phosphatidylinositol 3-kinase (PI 3-K), and the synthesis of its lipid products, is important in pathways mediating cell proliferation, survival, and motility. Alterations in PI 3-K mediated signaling are common to many cancers. Targeting PI 3-K activity is recognized as a potential anti-cancer strategy. The lipid products of PI 3-K act as second messengers by activating downstream protein effectors by their recruitment to specific domains in the plasma membrane. We propose a new strategy for inhibiting PI 3-K mediated signaling in disease by preventing the interaction of PI(3,4,5)P3 with these protein effectors. In vitro and cell-based assays will be developed to determine the interaction of selected effectors with PI(3,4,5)P3. These will be used to identify compounds which block the interaction of PI(3,4,5)P3 with effector proteins using libraries of synthetic small molecules and of compounds from natural sources. The mode of action of inhibitors will also be explored in cell culture. Identification and characterization of novel antagonists of PI 3-K signaling may lead to new therapies for cancer, inflammation, and diabetes.
Thesaurus Terms:
biological signal transduction, phosphatidylinositol, phospholipid inhibitor, technology /technique development
apoptosis, carcinogenesis, cell membrane, cell proliferation, enzyme activity, green fluorescent protein, intermolecular interaction, phosphatidylinositol 3 kinase, second messenger
flow cytometry, fluorescence resonance energy transfer, tissue /cell culture
Institution: ECHELON BIOSCIENCES, INC. 675 ARAPEEN DR, STE 302 SALT LAKE CITY, UT 84108 Fiscal Year: 2003 Department: Project Start: 01-FEB-2003 Project End: 31-JAN-2005 ICD: NATIONAL CANCER INSTITUTE IRG: ZCA1