PKB / Akt - SPR Binding Assay

Our service for comprehensive kinetic characterization of your small molecule kinase inhibitors

Theoretical background:Protein kinase B (PKB/Akt) is a serine/threonine protein kinase that encompasses three isoforms; PKBα (Akt1), PKBβ (Akt2) and PKBγ (Akt3). It is regulated mainly following activation of the second messenger phospholipid kinase phosphatidylinositol 3-kinase (PI3K) as well as by other regulatory proteins including Ras and PTEN.  PKB / Akt regulates many cellular processes including metabolism, proliferation, cell survival, growth and angiogenesis and has a key role in regulating glucose and lipid metabolism. A dysregulation of the kinase is associated with several human diseases including cancer, diabetes, as well as cardiovascular and neurological disorders.

 

PKB / Akt and inhibitors: Numerous ATP-competitive inhibitors have been developed for Akt (e.g. GSK690693, Akt1 IC50 = 2 nM [1] ). However, since the architecture of the ATP binding site of all protein kinases is very similar it is still challenging to identify a highly selective compound. Furthermore, the design of PH domain targeted inhibitors represents a promising approach. Triciribine phosphate (TCN-P), a tricyclic nucleoside inhibits the activation of all isoforms of Akt in cells by binding to the PH domain (KD = 690 nM [2]). A novel class of allosteric inhibitors which neither binds to the ATP binding site nor the PH domain (e.g. MK-2206, Akt1 IC50 = 5 nM [3] ) but to a site that is likely to be unique to Akt exhibit minimal activity towards other protein kinases. 

Figure: Real-time kinetic analysis of kinase inhibitor MK-2206 binding to PKBα / Akt1 using surface plasmon resonance.

 

[1] Rhodes et al. Cancer Res 2008;68:2366-2374

[2] Yan et al. AACR Annual Meeting 2009: Abstract Number: DDT01-1

[3] Berndt et al. (2010) Cell Death Differ. 17(11):1795-804.

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