Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes

Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry
Savvas N GeorgiadesRamón Vilar

Abstract

The discovery of small-molecule modulators of signaling pathways is currently a particularly active area of research. We aimed at developing unprecedented metal-based activators of Akt signaling which can potentially find applications as tools for regulating glucose metabolism downstream of Akt or serve as lead structures for developing antidiabetic drugs. In this context, a highly diverse library of 11 new zinc(II) complexes with phenolic, picolinic, pyridino, and hydroxamic ligands, all containing features beneficial for medicinal purposes, was prepared and screened in an assay that detected levels of phospho-Akt in lysates from NIH3T3 cells after treatment with the compounds. The complexes featuring hydroxamic ligands were found to be the most prominent activators of Akt among the molecules prepared, with the most efficient compound acting at submicromolar concentrations. Further characterization revealed that this compound induces phosphorylation of the Akt downstream effector glycogen synthase kinase 3β, but does not act as an inhibitor of tyrosine phosphatases or PTEN.

References

Dec 1, 1980·Journal of Medicinal Chemistry·N FinchH J Povalski
Aug 10, 1999·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·C CuncicC Ramachandran
Jan 27, 2000·Cell·Tony Hunter
Mar 15, 2001·Current Opinion in Cell Biology·Michael B Yaffe, A E Elia
Feb 28, 2002·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Yutaka YoshikawaYoshitane Kojima
May 8, 2002·Nature Reviews. Molecular Cell Biology·Michael B Yaffe
Dec 10, 2002·Science·G ManningS Sudarsanam
Nov 5, 2003·Biochemistry·Laiping XieZhong-Yin Zhang
May 19, 2004·FEBS Letters·Annette C SchmidRudiger Woscholski
Jun 10, 2004·Cell·Andres AlonsoTomas Mustelin
May 27, 2005·Journal of Inorganic Biochemistry·Misaki NakaiShigenobu Yano
Sep 3, 2005·Chemical Society Reviews·David R Spring
Sep 15, 2005·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Hajo Haase, Wolfgang Maret
Oct 15, 2005·Biotechnology and Bioengineering·Victor V T WongMiranda G S Yap
Sep 16, 2006·Archives of Biochemistry and Biophysics·Philippe L WalterLars-Oliver Klotz
Jan 24, 2007·ACS Chemical Biology·Erika RosivatzRudiger Woscholski
Feb 24, 2007·Journal of Inorganic Biochemistry·Wanny BasukiHiromu Sakurai
Jan 17, 2008·Chemical Society Reviews·Sheshanath V BhosaleSteven J Langford
Feb 22, 2008·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Akihiro NakayamaHiromu Sakurai
Apr 15, 2008·International Journal of Radiation Oncology, Biology, Physics·Theodore E Yaeger
Oct 22, 2008·Nature Chemical Biology·Joseph LehárCorey Nislow
Oct 25, 2008·Chemical Society Reviews·Hiromu SakuraiHiroyuki Yasui
Dec 18, 2008·Chemical Society Reviews·Michael HambourgerThomas A Moore
Jun 6, 2009·Annual Review of Biochemistry·Mary Katherine Tarrant, Philip A Cole
Jul 2, 2009·Journal of Chemical Biology·Richard M Gunn, Helen C Hailes
Jul 15, 2009·Cell Cycle·Eva Gonzalez, Timothy E McGraw
Jun 7, 2011·Journal of Chemical Biology·Lok Hang MakRudiger Woscholski

Related Concepts

Hydroxamic Acids
Organometallic Compounds
Phosphorylation
Zinc
Phosphatidylinositol 3-Kinases
NIH 3T3 Cells
Protein kinase B gamma
Ligands
Metals
Plants, Medicinal

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