2f7z
From Proteopedia
(New page: 200px<br /><applet load="2f7z" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f7z, resolution 3.00Å" /> '''Protein Kinase A bou...) |
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| - | [[Image:2f7z.gif|left|200px]]<br /><applet load="2f7z" size=" | + | [[Image:2f7z.gif|left|200px]]<br /><applet load="2f7z" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2f7z, resolution 3.00Å" /> | caption="2f7z, resolution 3.00Å" /> | ||
'''Protein Kinase A bound to (R)-1-(1H-Indol-3-ylmethyl)-2-(2-pyridin-4-yl-[1,7]naphtyridin-5-yloxy)-ehylamine'''<br /> | '''Protein Kinase A bound to (R)-1-(1H-Indol-3-ylmethyl)-2-(2-pyridin-4-yl-[1,7]naphtyridin-5-yloxy)-ehylamine'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Structure-based design and synthesis of the 3,4'-bispyridinylethylene | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2F7Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with 6EA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http:// | + | 2F7Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=6EA:'>6EA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F7Z OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Dinges, J.]] | [[Category: Dinges, J.]] | ||
[[Category: Fisher, J.]] | [[Category: Fisher, J.]] | ||
| - | [[Category: Giranda, V | + | [[Category: Giranda, V L.]] |
[[Category: Gong, J.]] | [[Category: Gong, J.]] | ||
| - | [[Category: Jakob, C | + | [[Category: Jakob, C G.]] |
| - | [[Category: Johnson, E | + | [[Category: Johnson, E F.]] |
| - | [[Category: Jong, R | + | [[Category: Jong, R Des.]] |
[[Category: Klinghofer, V.]] | [[Category: Klinghofer, V.]] | ||
[[Category: Li, Q.]] | [[Category: Li, Q.]] | ||
| Line 29: | Line 29: | ||
[[Category: Oltersdorf, T.]] | [[Category: Oltersdorf, T.]] | ||
[[Category: Packard, G.]] | [[Category: Packard, G.]] | ||
| - | [[Category: Rosenberg, S | + | [[Category: Rosenberg, S H.]] |
[[Category: Shi, Y.]] | [[Category: Shi, Y.]] | ||
[[Category: Song, X.]] | [[Category: Song, X.]] | ||
| - | [[Category: Stoll, V | + | [[Category: Stoll, V S.]] |
[[Category: Thomas, S.]] | [[Category: Thomas, S.]] | ||
| - | [[Category: Woods, K | + | [[Category: Woods, K W.]] |
| - | [[Category: Zhu, G | + | [[Category: Zhu, G D.]] |
[[Category: 6EA]] | [[Category: 6EA]] | ||
[[Category: akt inhibitors]] | [[Category: akt inhibitors]] | ||
[[Category: protein kinase a]] | [[Category: protein kinase a]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:18:37 2008'' |
Revision as of 15:18, 21 February 2008
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Protein Kinase A bound to (R)-1-(1H-Indol-3-ylmethyl)-2-(2-pyridin-4-yl-[1,7]naphtyridin-5-yloxy)-ehylamine
Overview
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.
About this Structure
2F7Z is a Single protein structure of sequence from Bos taurus with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
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., Li Q, Woods KW, Thomas S, Zhu GD, Packard G, Fisher J, Li T, Gong J, Dinges J, Song X, Abrams J, Luo Y, Johnson EF, Shi Y, Liu X, Klinghofer V, Des Jong R, Oltersdorf T, Stoll VS, Jakob CG, Rosenberg SH, Giranda VL, Bioorg Med Chem Lett. 2006 Apr 1;16(7):2000-7. Epub 2006 Jan 18. PMID:16413780
Page seeded by OCA on Thu Feb 21 17:18:37 2008
Categories: Bos taurus | Non-specific serine/threonine protein kinase | Single protein | Abrams, J. | Dinges, J. | Fisher, J. | Giranda, V L. | Gong, J. | Jakob, C G. | Johnson, E F. | Jong, R Des. | Klinghofer, V. | Li, Q. | Li, T. | Liu, X. | Luo, Y. | Oltersdorf, T. | Packard, G. | Rosenberg, S H. | Shi, Y. | Song, X. | Stoll, V S. | Thomas, S. | Woods, K W. | Zhu, G D. | 6EA | Akt inhibitors | Protein kinase a
