Selective small molecule compounds increase BMP-2 responsiveness by inhibiting Smurf1-mediated Smad1/5 degradation

Sci Rep. 2014 May 14;4:4965. doi: 10.1038/srep04965.

Abstract

The ubiquitin ligase Smad ubiquitination regulatory factor-1 (Smurf1) negatively regulates bone morphogenetic protein (BMP) pathway by ubiquitinating certain signal components for degradation. Thus, it can be an eligible pharmacological target for increasing BMP signal responsiveness. We established a strategy to discover small molecule compounds that block the WW1 domain of Smurf1 from interacting with Smad1/5 by structure based virtual screening, molecular experimental examination and cytological efficacy evaluation. Our selected hits could reserve the protein level of Smad1/5 from degradation by interrupting Smurf1-Smad1/5 interaction and inhibiting Smurf1 mediated ubiquitination of Smad1/5. Further, these compounds increased BMP-2 signal responsiveness and the expression of certain downstream genes, enhanced the osteoblastic activity of myoblasts and osteoblasts. Our work indicates targeting Smurf1 for inhibition could be an accessible strategy to discover BMP-sensitizers that might be applied in future clinical treatments of bone disorders such as osteopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 2 / metabolism*
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Protein Interaction Domains and Motifs / drug effects
  • Protein Structure, Tertiary / drug effects
  • Proteolysis / drug effects*
  • Signal Transduction / drug effects
  • Smad1 Protein / metabolism*
  • Smad5 Protein / metabolism*
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • SMAD1 protein, human
  • SMAD5 protein, human
  • Smad1 Protein
  • Smad5 Protein
  • Small Molecule Libraries
  • SMURF1 protein, human
  • Ubiquitin-Protein Ligases