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Review
. 2011 May;3(7):821-33.
doi: 10.4155/fmc.11.47.

Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease

Michael Voronkov  1 , Steven P Braithwaite, Jeffry B Stock
Affiliations
Review

Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease

Michael Voronkov et al. Future Med Chem. 2011 May.

Abstract

Tau hyperphosphorylation is thought to play an important role in the etiology of Alzheimer's disease by facilitating the formation of neurofibrillary tangles. Reducing phosphorylation through kinase inhibition has therefore emerged as a target for drug development, but despite considerable efforts to develop therapeutic kinase inhibitors, success has been limited. An alternative approach is to develop pharmaceuticals to enhance the activity of the principal phospho-tau phosphatase, phosphoprotein phosphatase 2A (PP2A). In this article we review evidence that this mechanism is pharmacologically achievable and has promise for delivering the next generation of Alzheimer's disease therapeutics. A number of different chemotypes have been reported to lead to enhanced PP2A activity through a range of proposed mechanisms. Some of these compounds appear to act directly as allosteric activators of PP2A, while others act indirectly by inhibiting the binding of PP2A inhibitors or by altering post-translational modifications that act in turn to regulate PP2A activity towards phospho-tau. These results indicate that PP2A may provide a useful target that can be safely, selectively and effectively modulated through pharmaceutical intervention to treat Alzheimer's disease.

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Conflict of interest statement

Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1
Figure 1. PP2A is a heterotrimeric holoenzyme that is regulated by multiple endogenous mechanisms
Catalytic C subunit (green), scaffolding A unit (red) and regulatory B subunit (blue) form the trimeric enzyme.
Figure 2
Figure 2. Major classes of PP2A activating compounds
Exemplifying structures of compounds in each class.
Figure 3
Figure 3. Physiochemical properties of molecules interacting directly with PP2A
(A) Compound distribution according to total polar surface area, and cLogP. (B) Compound distribution predicts BBB permeability, by LogBBB against cLogP, total polar surface area and cLogP were calculated using JChem software. LogBBB was calculated as in [101]. BBB: Blood–brain barrier.
See this image and copyright information in PMC

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