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

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.

► We developed SNIPER-4 that targets CRABP-II for proteasomal degradation. ► SNIPER-4 consists of MeBS and ATRA that bind to cIAP1 and CRABP-II, respectively. ► SNIPER-4 induces ubiquitylation of CRABP-II by cIAP1. ► SNIPER-4 does not induce cIAP1 degradation. ► Protein knockdown can be attained by small molecules based on the SNIPER-4.