As cancer is one of the leading causes of death in the United States with some sub-types remaining essentially untreatable, expansion of available drug targets will provide significant new options for the development of more effective antineoplastic agents. The major goal of this project is to apply a unique drug discovery strategy to cancer drug development. This will be accomplished through application of this methodology to the discovery and characterization of new drug-like small molecule therapeutics disrupting interactions relevant to anti-cancer therapy. Improved strategies for developing pharmaceuticals based on inhibitors of protein-protein interactions would be beneficial in order to overcome the limitations of the majority of currently druggable targets to those involving ligand-receptor and enzyme-substrate interactions. We will focus our efforts on the Cyclin Dependent Kinase substrate recruitment site as a validated antitumor drug target. Through this site, the opportunity exists to develop potent and selective inhibitors that are specific to the cell cycle CDKs. Such compounds possessing appropriate drug-like characteristics will potentially be different mechanistically from ATP competitive CDK inhibitors, targeting tumor cells selectively and thereby addressing issues with agents currently being developed.

Public Health Relevance

The major goal of this project is extend and further validate a unique drug discovery strategy for blocking the association of protein-protein complexes and to apply this methodology to discover new drug-like small molecule therapeutics disrupting such interactions relevant to anti-cancer therapy. We will focus on the Cyclin Dependent Kinase substrate recruitment site, through which the opportunity exists to develop potent and selective inhibitors that are specific to the cell cycle CDKs. Such compounds possessing appropriate drug-like characteristics will be different mechanistically from ATP competitive CDK inhibitors, targeting tumor cells selectively and addressing issues with agents currently being developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131368-04
Application #
8117089
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2008-09-25
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$272,007
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Nandha Premnath, Padmavathy; Craig, Sandra; McInnes, Campbell (2015) Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors. J Vis Exp :e52441
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