2F7Z

Protein Kinase A bound to (R)-1-(1H-Indol-3-ylmethyl)-2-(2-pyridin-4-yl-[1,7]naphtyridin-5-yloxy)-ehylamine

Summary for 2F7Z

• Entry DOI: 10.2210/pdb2f7z/pdb
• Related: 2F7E 2F7X
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, PKI, inhibitory peptide, (1S)-1-(1H-INDOL-3-YLMETHYL)-2-(2-PYRIDIN-4-YL-[1,7]NAPHTYRIDIN-5-YLOXY)-EHYLAMINE (3 entities in total)
• Functional Keywords: protein kinase a, akt inhibitors, transferase
• Biological source: Bos taurus (cattle)
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43299.52

Authors

Li, Q.,Woods, K.W.,Thomas, S.,Zhu, G.D.,Packard, G.,Fisher, J.,Li, T.,Gong, J.,Dinges, J.,Song, X.,Abrams, J.,Luo, Y.,Johnson, E.F.,Shi, Y.,Liu, X.,Klinghofer, V.,Des Jong, R.,Oltersdorf, T.,Stoll, V.S.,Jakob, C.G.,Rosenberg, S.H.,Giranda, V.L. (deposition date: 2005-12-01, release date: 2006-06-27, Last modification date: 2024-02-14)

Primary citation

Li, Q.,Woods, K.W.,Thomas, S.,Zhu, G.D.,Packard, G.,Fisher, J.,Li, T.,Gong, J.,Dinges, J.,Song, X.,Abrams, J.,Luo, Y.,Johnson, E.F.,Shi, Y.,Liu, X.,Klinghofer, V.,Des Jong, R.,Oltersdorf, T.,Stoll, V.S.,Jakob, C.G.,Rosenberg, S.H.,Giranda, V.L.
Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer.
Bioorg.Med.Chem.Lett., 16:2000-2007, 2006

PubMed Abstract: Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.

PubMed: 16413780
DOI: 10.1016/j.bmcl.2005.12.065

Experimental method

X-RAY DIFFRACTION (3 Å)