2uzu

File:2uzu.gif

spinqualitylabelsall models 2uzu, resolution 2.4Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PKA STRUCTURES OF INDAZOLE-PYRIDINE SERIES OF AKT INHIBITORS

OverviewOverview

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. ... [(full description)]

About this StructureAbout this Structure

2UZU is a [Protein complex] structure of sequences from [Bos taurus] with L20 as [ligand]. Active as [cAMP-dependent protein kinase], with EC number [2.7.11.11]. Structure known Active Site: AC1. Full crystallographic information is available from [OCA].

ReferenceReference

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

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