Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents

Clin Sci (Lond). 2021 Jul 16;135(13):1545-1556. doi: 10.1042/CS20201367.


Tumor initiation is driven by oncogenes that activate signaling networks for cell proliferation and survival involving protein phosphorylation. Protein kinases in these pathways have proven to be effective targets for pharmaceutical inhibitors that have progressed to the clinic to treat various cancers. Here, we offer a narrative about the development of small molecule modulators of the protein Ser/Thr phosphatase 2A (PP2A) to reduce the activation of cell proliferation and survival pathways. These novel drugs promote the assembly of select heterotrimeric forms of PP2A that act to limit cell proliferation. We discuss the potential for the near-term translation of this approach to the clinic for cancer and other human diseases.

Keywords: drug development; enzyme activation; protein phosphatases; protein phosphorylation.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Conformation
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Protein Phosphatase 2 / chemistry
  • Protein Phosphatase 2 / metabolism
  • Signal Transduction
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Protein Phosphatase 2