Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta

Li Fan Zeng, Ruo Yu Zhang, Yunpeng Bai, Li Wu, Andrea M. Gunawan, Zhong Yin Zhang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aims: Protein tyrosine phosphatases (PTPs) play an important role in regulating a wide range of cellular processes. Understanding the role of PTPs within these processes has been hampered by a lack of potent and selective PTP inhibitors. Generating potent and selective probes for PTPs remains a significant challenge because of the highly conserved and positively charged PTP active site that also harbors a redox-sensitive Cys residue. Results: We describe a facile method that uses an appropriate hydroxyindole carboxylic acid to anchor the inhibitor to the PTP active site and relies on the secondary binding elements introduced through an amide-focused library to enhance binding affinity for the target PTP and to impart selectivity against off-target phosphatases. Here, we disclose a novel series of hydroxyindole carboxylic acid-based inhibitors for receptor-type tyrosine protein phosphatase beta (RPTPβ), a potential target that is implicated in blood vessel development. The representative RPTPβ inhibitor 8b-1 (L87B44) has an IC50 of 0.38âμM and at least 14-fold selectivity for RPTPβ over a large panel of PTPs. Moreover, 8b-1 also exhibits excellent cellular activity and augments growth factor signaling in HEK293, MDA-MB-468, and human umbilical vein endothelial cells. Innovation: The bicyclic salicylic acid pharmacophore-based focused library approach may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. Conclusion: A novel method is described for the development of bioavailable PTP inhibitors that utilizes bicyclic salicylic acid to anchor the inhibitors to the active site and peripheral site interactions to enhance binding affinity and selectivity. Antioxid. Redox Signal. 20, 2130-2140.

Original languageEnglish (US)
Pages (from-to)2130-2140
Number of pages11
JournalAntioxidants and Redox Signaling
Volume20
Issue number14
DOIs
StatePublished - May 10 2014

Fingerprint

Class 5 Receptor-Like Protein Tyrosine Phosphatases
Protein Tyrosine Phosphatases
Carboxylic Acids
Proteins
Catalytic Domain
Salicylic Acid
Anchors
Libraries
Oxidation-Reduction
Endothelial cells
Human Umbilical Vein Endothelial Cells
Blood vessels
Drug Discovery
Ports and harbors
Phosphoric Monoester Hydrolases
Amides
Biological Availability
Inhibitory Concentration 50
Blood Vessels
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta. / Zeng, Li Fan; Zhang, Ruo Yu; Bai, Yunpeng; Wu, Li; Gunawan, Andrea M.; Zhang, Zhong Yin.

In: Antioxidants and Redox Signaling, Vol. 20, No. 14, 10.05.2014, p. 2130-2140.

Research output: Contribution to journalArticle

Zeng, Li Fan ; Zhang, Ruo Yu ; Bai, Yunpeng ; Wu, Li ; Gunawan, Andrea M. ; Zhang, Zhong Yin. / Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta. In: Antioxidants and Redox Signaling. 2014 ; Vol. 20, No. 14. pp. 2130-2140.
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