One of the biggest challenges in biomedical research is to design ligands for novel molecular targets so as to better understand the molecular mechanisms of life-threatening diseases and develop innovative, more effective treatments. Regrettably, progress along this line has been slow / among the approximately 50 new drugs approved by the Food and Drug Administration each year, only 3 - 5 address a new molecular target. SUMO (Small Ubiquitin-like Modifier) is one of the newly identified targets with importance in treating cancer and viral infection, for which inhibitors have not been developed to date. Protein modifications by the SUMO family of proteins regulate essential functions such as gene transcription, cell cycle progression and DNA repair. Our preliminary data has shown that inhibition of SUMO-mediated protein-protein interactions can inhibit DNA repair and sensitize cancer cells to chemotherapy and radiation. The overall goal of the proposal is to develop high throughput screening (HTS) assays to identify inhibitors for SUMO-dependent protein-protein interactions. Inhibitors of the homologous ubiquitin-proteosome pathway have been critical in studies of ubiquitin- dependent degradation and have also been extremely successful as anti-cancer therapeutics. Inhibitors of SUMO-dependent protein-protein interactions hold similar promise and could lead to the establishment of a new paradigm in the treatment of human diseases. We propose to develop HTS assays using the AlphaScreen technology, fluorescence resonance energy transfer and cell- based high content imaging approaches to identify such inhibitors. These assays will be used in automated high throughput screening (HTS) by the Molecular Libraries Production Centers Network (MLPCN). We will also perform studies using cellular and animal models to determine the research and therapeutic potentials of the lead inhibitors identified from HTS.

Public Health Relevance

The overall goal of this proposal is to develop high throughput screening assays (HTS) to identify inhibitors for SUMO-mediated protein-protein interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21NS066498-01S1
Application #
8413730
Study Section
Special Emphasis Panel (ZRG1-BST-J (51))
Program Officer
Scheideler, Mark A
Project Start
2009-06-05
Project End
2014-01-31
Budget Start
2009-06-05
Budget End
2014-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$41,500
Indirect Cost
$16,500
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010