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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007, Vol.17 (1), p.225-230
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2006.09.056