Abstract
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
MeSH terms
-
CD4-Positive T-Lymphocytes / drug effects
-
CD4-Positive T-Lymphocytes / enzymology
-
CD4-Positive T-Lymphocytes / immunology
-
Humans
-
Interleukin-2 / metabolism
-
Isoenzymes / antagonists & inhibitors*
-
Models, Molecular
-
Molecular Structure
-
Protein Conformation
-
Protein Kinase C / antagonists & inhibitors*
-
Protein Kinase C-theta
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacology*
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacology*
-
Structure-Activity Relationship
Substances
-
Interleukin-2
-
Isoenzymes
-
Protein Kinase Inhibitors
-
Pyrimidines
-
PRKCQ protein, human
-
Protein Kinase C
-
Protein Kinase C-theta