Heterobifunctional Molecules Induce Dephosphorylation of Kinases-A Proof of Concept Study

J Med Chem. 2020 Mar 26;63(6):2807-2813. doi: 10.1021/acs.jmedchem.9b01167. Epub 2020 Jan 14.

Abstract

Heterobifunctional molecules have proven powerful tools to induce ligase-dependent ubiquitination of target proteins. We describe here a chemical strategy for controlling a different post-translational modification (PTM): phosphorylation. Heterobifunctional molecules were designed to promote the proximity of a protein phosphatase (PP1) to protein targets. The synthesized molecules induced the PP1-dependent dephosphorylation of AKT and EGFR. To our knowledge, this work represents the first examples of small molecules recruiting non-native partners to induce removal of a PTM.

MeSH terms

  • Cell Line
  • Drug Discovery*
  • ErbB Receptors / metabolism
  • Humans
  • Ligands
  • Phosphorylation / drug effects*
  • Phosphotransferases / metabolism*
  • Proof of Concept Study
  • Protein Phosphatase 1 / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Ligands
  • Small Molecule Libraries
  • Phosphotransferases
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 1