Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein

FEBS Lett. 2011 Apr 20;585(8):1147-52. doi: 10.1016/j.febslet.2011.03.019. Epub 2011 Mar 21.

Abstract

Manipulation of protein stability with small molecules is a challenge in the field of drug discovery. Here we show that cellular retinoic acid binding protein-II (CRABP-II) can be specifically degraded by a novel compound, SNIPER-4, consisting of (--)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-L-leucine methyl ester and all-trans retinoic acid that are ligands for cellular inhibitor of apoptosis protein 1 (cIAP1) and CRABP-II, respectively. Mechanistic analysis revealed that SNIPER-4 induces cIAP1-mediated ubiquitylation of CRABP-II, resulting in the proteasomal degradation. The protein knockdown strategy employing the structure of SNIPER-4 could be applicable to other target proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cross-Linking Reagents / chemistry
  • Cross-Linking Reagents / pharmacology
  • Humans
  • Immunoblotting
  • Inhibitor of Apoptosis Proteins / chemistry
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Leucine / analogs & derivatives
  • Leucine / chemistry
  • Leucine / pharmacology
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Stability / drug effects
  • RNA Interference
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Tretinoin / chemistry
  • Tretinoin / pharmacology
  • Ubiquitination / drug effects

Substances

  • (-)-N-((2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl)-L-leucine methyl ester
  • Cross-Linking Reagents
  • Inhibitor of Apoptosis Proteins
  • Receptors, Retinoic Acid
  • retinoic acid binding protein II, cellular
  • Tretinoin
  • Proteasome Endopeptidase Complex
  • Leucine