Pyrazolopyrimidines as dual Akt/p70S6K inhibitors

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through rel...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (8), p.2693-2697
Hauptverfasser:	Rice, Kenneth D., Kim, Moon H., Bussenius, Joerg, Anand, Neel K., Blazey, Charles M., Bowles, Owen J., Canne-Bannen, Lynne, Chan, Diva S.-M., Chen, Baili, Co, Erick W., Costanzo, Simona, DeFina, Steven C., Dubenko, Larisa, Engst, Stefan, Franzini, Maurizio, Huang, Ping, Jammalamadaka, Vasu, Khoury, Richard G., Klein, Rhett R., Laird, A.Douglas, Le, Donna T., Mac, Morrison B., Matthews, David J., Markby, David, Miller, Nicole, Nuss, John M., Parks, Jason J., Tsang, Tsze H., Tsuhako, Amy L., Wang, Yong, Xu, Wei
Format:	Artikel
Sprache:	eng
Schlagworte:	Akt inhibitor Animals Antineoplastic agents Biological and medical sciences Cancer Dogs Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Haplorhini Humans Medical sciences Mice Microsomes - drug effects Models, Molecular Molecular Structure p70S6K inhibitor Pharmacology. Drug treatments Phosphatidylinositol 3-Kinases - drug effects PI3K pathway Proto-Oncogene Proteins c-akt - antagonists & inhibitors Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyrazolopyrimidine Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.03.011