2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics

The development of a series of potent AKT1 inhibitors is reported. A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several comp...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1652-1656
Hauptverfasser:	Zeng, Qingping, Bourbeau, Matthew P., Wohlhieter, G. Erich, Yao, Guomin, Monenschein, Holger, Rider, James T., Lee, Matthew R., Zhang, Shiwen, Lofgren, Julie, Freeman, Daniel, Li, Chun, Tominey, Elizabeth, Huang, Xin, Hoffman, Douglas, Yamane, Harvey, Tasker, Andrew S., Dominguez, Celia, Viswanadhan, Vellarkad N., Hungate, Randall, Zhang, Xiaoling
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Biological and medical sciences Catalytic Domain Crystallography, X-Ray Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors Cyclic AMP-Dependent Protein Kinases - metabolism Cyclin-Dependent Kinase 2 - antagonists & inhibitors Cyclin-Dependent Kinase 2 - metabolism General aspects Isoquinolines - chemical synthesis Isoquinolines - chemistry Isoquinolines - pharmacokinetics Medical sciences Mice Neoplasms - drug therapy Pharmacology. Drug treatments Phosphorylation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Rats Structure-Activity Relationship Thiadiazoles - chemical synthesis Thiadiazoles - chemistry Thiadiazoles - pharmacokinetics Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacokinetics
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	The development of a series of potent AKT1 inhibitors is reported. A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.01.046