2uzt

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:2uzt.jpg|left|200px]]
+
{{Seed}}
 +
[[Image:2uzt.png|left|200px]]
<!--
<!--
Line 9: Line 10:
{{STRUCTURE_2uzt| PDB=2uzt | SCENE= }}
{{STRUCTURE_2uzt| PDB=2uzt | SCENE= }}
-
'''PKA STRUCTURES OF AKT, INDAZOLE-PYRIDINE INHIBITORS'''
+
===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.
+
The line below this paragraph, {{ABSTRACT_PUBMED_17523610}}, adds the Publication Abstract to the page
 +
(as it appears on PubMed at http://www.pubmed.gov), where 17523610 is the PubMed ID number.
 +
-->
 +
{{ABSTRACT_PUBMED_17523610}}
==About this Structure==
==About this Structure==
Line 60: Line 64:
[[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 Sun May 4 17:53:49 2008''
+
 
 +
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 16:22:31 2008''

Revision as of 13:22, 28 July 2008

Image:2uzt.png

Template:STRUCTURE 2uzt

PKA STRUCTURES OF AKT, INDAZOLE-PYRIDINE INHIBITORS

Template:ABSTRACT PUBMED 17523610

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 Mon Jul 28 16:22:31 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2uzt"
Personal tools