Using small molecules to target protein phosphatases

Bioorg Med Chem. 2011 Apr 1;19(7):2145-55. doi: 10.1016/j.bmc.2011.02.047. Epub 2011 Mar 2.


The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations.

MeSH terms

  • Animals
  • Drug Delivery Systems
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Targeted Therapy / methods
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / metabolism
  • Rats


  • Enzyme Inhibitors
  • Protein Tyrosine Phosphatases