- 2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.
2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.
Bioorganic & medicinal chemistry letters (2010-02-09)
Qingping Zeng, Matthew P Bourbeau, G Erich Wohlhieter, Guomin Yao, Holger Monenschein, James T Rider, Matthew R Lee, Shiwen Zhang, Julie Lofgren, Daniel Freeman, Chun Li, Elizabeth Tominey, Xin Huang, Douglas Hoffman, Harvey Yamane, Andrew S Tasker, Celia Dominguez, Vellarkad N Viswanadhan, Randall Hungate, Xiaoling Zhang
PMID20137932
RESUMEN
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.
MATERIALES