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.
- Cellular inhibitor of apoptosis protein 1
- Cellular retinoic acid binding protein-II
- Protein knockdown
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology
- Cell Biology