2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.
| Autor: | Zeng Q; Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA., Bourbeau MP, Wohlhieter GE, Yao G, Monenschein H, Rider JT, Lee MR, Zhang S, Lofgren J, Freeman D, Li C, Tominey E, Huang X, Hoffman D, Yamane H, Tasker AS, Dominguez C, Viswanadhan VN, Hungate R, Zhang X |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Mar 01; Vol. 20 (5), pp. 1652-6. Date of Electronic Publication: 2010 Jan 20. |
| DOI: | 10.1016/j.bmcl.2010.01.046 |
| Abstrakt: | 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. (Copyright 2010 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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