Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2885-91. doi: 10.1016/j.bmcl.2014.04.089. Epub 2014 May 2.

Abstract

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.

Keywords: A1120; Fenretinide; Non-retinoid; RBP4; Small molecules.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Ligands
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Retinol-Binding Proteins, Plasma / antagonists & inhibitors*
  • Retinol-Binding Proteins, Plasma / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Vitamin A / blood

Substances

  • Ligands
  • RBP4 protein, human
  • Rbp4 protein, mouse
  • Retinol-Binding Proteins, Plasma
  • Small Molecule Libraries
  • Vitamin A