2uzt
From Proteopedia
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| - | [[Image:2uzt.jpg|left|200px]] | + | [[Image:2uzt.jpg|left|200px]] |
| - | + | ||
| - | '''PKA STRUCTURES OF AKT, INDAZOLE-PYRIDINE INHIBITORS''' | + | {{Structure |
| + | |PDB= 2uzt |SIZE=350|CAPTION= <scene name='initialview01'>2uzt</scene>, resolution 2.1Å | ||
| + | |SITE= <scene name='pdbsite=AC1:Ss3+Binding+Site+For+Chain+A'>AC1</scene> | ||
| + | |LIGAND= <scene name='pdbligand=SS3:(2S)-1-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}-3-PHENYLPROPAN-2-AMINE'>SS3</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''PKA STRUCTURES OF AKT, INDAZOLE-PYRIDINE INHIBITORS''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2UZT is a [ | + | 2UZT is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UZT OCA]. |
==Reference== | ==Reference== | ||
| - | Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension., Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Bouska J, Olson A, Marsh KC, Stoll VS, Mamo M, Polakowski J, Campbell TJ, Martin RL, Gintant GA, Penning TD, Li Q, Rosenberg SH, Giranda VL, J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25. PMID:[http:// | + | Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension., Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Bouska J, Olson A, Marsh KC, Stoll VS, Mamo M, Polakowski J, Campbell TJ, Martin RL, Gintant GA, Penning TD, Li Q, Rosenberg SH, Giranda VL, J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17523610 17523610] |
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: Zhu, G D.]] | [[Category: Zhu, G D.]] | ||
[[Category: SS3]] | [[Category: SS3]] | ||
| - | [[Category: akt | + | [[Category: akt inhibitor]] |
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
[[Category: camp]] | [[Category: camp]] | ||
| Line 48: | Line 57: | ||
[[Category: nucleotide-binding]] | [[Category: nucleotide-binding]] | ||
[[Category: phosphorylation]] | [[Category: phosphorylation]] | ||
| - | [[Category: protein kinase | + | [[Category: protein kinase some]] |
[[Category: protein kinase inhibitor]] | [[Category: protein kinase inhibitor]] | ||
[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:41:40 2008'' |
Revision as of 16:41, 20 March 2008
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| , resolution 2.1Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | |||||||
| Activity: | cAMP-dependent protein kinase, with EC number 2.7.11.11 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
PKA STRUCTURES OF AKT, INDAZOLE-PYRIDINE INHIBITORS
Overview
Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
About this Structure
2UZT is a Protein complex structure of sequences from Bos taurus. Full crystallographic information is available from OCA.
Reference
Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension., Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Bouska J, Olson A, Marsh KC, Stoll VS, Mamo M, Polakowski J, Campbell TJ, Martin RL, Gintant GA, Penning TD, Li Q, Rosenberg SH, Giranda VL, J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25. PMID:17523610
Page seeded by OCA on Thu Mar 20 18:41:40 2008
Categories: Bos taurus | Protein complex | CAMP-dependent protein kinase | Bouska, J. | Campbell, T J. | Diebold, R B. | Gandhi, V B. | Giranda, V L. | Gong, J. | Guan, R. | Johnson, E F. | Klinghofer, V. | Li, Q. | Li, T. | Liu, X. | Luo, Y. | Mamo, M. | Marsh, K C. | Olson, A. | Penning, T D. | Polakowski, J. | Rosenberg, S H. | Song, X. | Stoll, V S. | Thomas, S. | Woods, K W. | Zhu, G D. | SS3 | Akt inhibitor | Atp-binding | Camp | Kinase | Lipoprotein | Myristate | Nuclear protein | Nucleotide-binding | Phosphorylation | Protein kinase some | Protein kinase inhibitor | Serine/threonine-protein kinase | Transferase
