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Review
. 2013 May;23(5):569-80.
doi: 10.1517/13543776.2013.768985. Epub 2013 Feb 5.

PTEN modulators: a patent review

Chandra S Boosani  1 , Devendra K Agrawal
Affiliations
Review

PTEN modulators: a patent review

Chandra S Boosani et al. Expert Opin Ther Pat. 2013 May.

Abstract

Introduction: PTEN (phosphatase and tensin homolog deleted on chromosome 10) plays a pivotal role in controlling intracellular signaling for cell survival and proliferation by inhibiting the PI3K/Akt pathway, and its dysfunction is associated with several neoplastic diseases. PTEN is frequently found mutated in many pathological conditions highlighting its importance in normal physiological function. Unlike several cellular proteins which are activated by phosphorylation, PTEN is inactivated upon phosphorylation by specific kinases which phosphorylate serine and threonine residues in its C-terminal region. Therefore, development of therapeutic agents that specifically target kinases and kinase-domain-containing proteins affecting PTEN would lead to the treatment of PTEN-related diseases.

Areas covered: With increasing evidence on the role of PTEN in many human diseases, the present review focuses on the clinical relevance of PTEN with a comprehensive list of currently identified modulators of PTEN, and proposes potentially novel molecular targets which could aid in the development of drug candidates for the treatment of PTEN-related diseases such as cardiovascular diseases, diabetes, obesity, cancer, autism, Parkinson's and Alzheimer's diseases.

Expert opinion: This review describes several target sites that could help in the development of novel drug candidates to regulate or restore the normal physiological functions of PTEN and are essential in the treatment of human diseases where PTEN plays a pivotal role.

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Conflict of interest statement

Declaration of interest

The authors declare no conflict of interest. Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers R01HL090580, R01HL104516, and R01HL112597.

Figures

Figure 1
Figure 1
A. Represents the Chain A structure of PTEN with PDB id “1D5R” with P-loop, WPD-loop and TI-loops, as highlighted, which are phosphatase characteristic regions. B. Shows specific residues that are phosphorylated by different kinases in the C-terminal tail region of PTEN. The panel B also shows the possible β-sheet structural features of the C-terminal tail region. C. Illustrates membrane binding and activation of PTEN which leads to inhibition of cellular pathways that are associated with specific human diseases, as described.
Figure 2
Figure 2. PTEN inhibits different cellular pathways
The inhibitory role of PTEN is highlighted to indicate its molecular targets in cellular signaling pathways that affect cell migration, proliferation, survival and protein synthesis.
Figure 3
Figure 3. PTEN modulation by kinases or kinase-domain-containing proteins
Different intracellular proteins that target PTEN to inhibit or activate its cellular functions are shown. This inhibition or activation of PTEN functions is primarily mediated through phosphorylation of specific residues in its C-terminal region.
Figure 4
Figure 4. Role of PTEN in type 2 diabetes
Figure shows the intracellular insulin regulation pathway and the interference of PTEN through the regulation of glucose metabolism.
See this image and copyright information in PMC

References

    1. Wiencke JK, Zheng S, Jelluma N, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neurol Oncol. 2007;9(3):271–9. - PMC - PubMed
    1. Tamguney T, Stokoe D. New insights into PTEN. J Cell Sci. 2007;120(Pt 23):4071–9. Good commentary describing regulations of PTEN and its role in human diseases. - PubMed
    1. COSMIC: catalog of somatic mutations in cancer. Welcome Trust, Sanger Institute; Cambridge, UK: 2011. Available from: http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=PTEN [Cited 11 November 2012] • This interactive website shows different mutations that are identified in the PTEN gene.
    1. Tumorscape: copy number alterations across multiple cancer types. The Broad Institute of MIT and Harvard; US: Available from: http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf# [Cited 14 November 2012]
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