Strategies to make protein serine/threonine (PP1, calcineurin) and tyrosine phosphatases (PTP1B) druggable: achieving specificity by targeting substrate and regulatory protein interaction sites

Bioorganic & Medicinal Chemistry
Wolfgang Peti, Rebecca Page

Abstract

The established dogma is that protein serine/threonine (PSPs) and tyrosine (PTPs) phosphatases are unattainable drug targets. This is because natural product inhibitors of PSP active sites are lethal, while the active sites of PTPs are exceptionally conserved and charged, making it nearly impossible to develop PTP inhibitors that are selective. However, due to a series of recent structural and functional studies, this view of phosphatases is about to undergo a radical change. Rather than target active sites, these studies have demonstrated that targeting PSP/PTP protein (substrate/regulatory) interaction sites, which are distal from the active sites, are highly viable and suitable drugs targets. This is especially true for calcineurin (CN), in which the blockbuster immunosuppressant drugs FK506 and cyclosporin A were recently demonstrated to bind and block one of the key CN substrate interaction sites, the LxVP site. Additional studies show that this approach-targeting substrate and/or regulatory protein interaction sites-also holds incredible promise for protein phosphatase 1 (PP1)-related diseases. Finally, domains outside PTP catalytic domains have also recently been demonstrated to directly alter PTP activity. Collectively,...Continue Reading

References

Jul 7, 2001·Trends in Biochemical Sciences·M Bollen
Dec 10, 2002·Science·G ManningS Sudarsanam
Jun 10, 2004·Cell·Andres AlonsoTomas Mustelin
Oct 7, 2004·Neuropharmacology·Angus C NairnPaul Greengard
Oct 24, 2006·Nature Reviews. Molecular Cell Biology·Nicholas K Tonks
Oct 29, 2008·Biochemistry·Barbara DancheckWolfgang Peti
Apr 20, 2010·Trends in Biochemical Sciences·Mathieu BollenMonique Beullens
Dec 1, 2010·Trends in Cell Biology·Huiming LiPatrick G Hogan
Dec 18, 2012·Nucleic Acids Research·Nikki MinneboMathieu Bollen

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Citations

Oct 5, 2016·ACS Chemical Biology·Sara FahsMaja Köhn
Feb 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wiljan HendriksRafael Pulido
Sep 7, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·Maja Köhn
Feb 13, 2020·Natural Product Reports·Marjorie BruderDaniela B B Trivella
Jun 12, 2019·Nature Communications·Greg G JonesPablo Rodriguez-Viciana
Oct 24, 2018·Proceedings of the National Academy of Sciences of the United States of America·Lucy C YoungPablo Rodriguez-Viciana
Jun 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Isabel Boned Del RíoPablo Rodriguez-Viciana
Feb 17, 2021·Archives of Pharmacal Research·Chiranjeev SharmaSang J Chung
Dec 22, 2016·Structure·Xinru WangRebecca Page
Apr 30, 2020·Biochemistry·Victor A BeaumontJ Patrick Loria

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