Discovery of potent and selective PKC-θ inhibitors

An uHTS campaign was performed to identify selective inhibitors of PKC-θ. 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-θ inhibitors. A homology model and initial SAR is presented d...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 17; no. 1; pp. 225 - 230
Main Authors:	Cywin, Charles L., Dahmann, Georg, Prokopowicz, Anthony S., Young, Erick R.R., Magolda, Ronald L., Cardozo, Mario G., Cogan, Derek A., DiSalvo, Darren, Ginn, John D., Kashem, Mohammed A., Wolak, John P., Homon, Carol A., Farrell, Thomas M., Grbic, Heather, Hu, Hanbo, Kaplita, Paul V., Liu, Lisa H., Spero, Denice M., Jeanfavre, Deborah D., O’Shea, Kathy M., White, Della M., Woska, Joseph R., Brown, Maryanne L.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 2007
Subjects:	CD4-Positive T-Lymphocytes - drug effects CD4-Positive T-Lymphocytes - enzymology CD4-Positive T-Lymphocytes - immunology Hit to lead Humans Inhibitor Interleukin-2 - metabolism Isoenzymes - antagonists & inhibitors Kinase Models, Molecular Molecular Structure PKC-θ 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 PKC-θ Inhibitor Kinase Hit to lead
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Summary:	An uHTS campaign was performed to identify selective inhibitors of PKC-θ. 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-θ 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2006.09.056