TY - JOUR
T1 - Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein
AU - Okuhira, Keiichiro
AU - Ohoka, Nobumichi
AU - Sai, Kimie
AU - Nishimaki-Mogami, Tomoko
AU - Itoh, Yukihiro
AU - Ishikawa, Minoru
AU - Hashimoto, Yuichi
AU - Naito, Mikihiko
N1 - Funding Information:
We thank Nippon Kayaku Co. Ltd. , for kindly providing MeBS. This study was supported in part by Grants-in-Aids for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan , and by the research grant of Astellas Foundation for Research on Metabolic Disorders.
PY - 2011/4/20
Y1 - 2011/4/20
N2 - 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.
AB - 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.
KW - Cellular inhibitor of apoptosis protein 1
KW - Cellular retinoic acid binding protein-II
KW - Proteasome
KW - Protein knockdown
KW - Ubiquitin
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U2 - 10.1016/j.febslet.2011.03.019
DO - 10.1016/j.febslet.2011.03.019
M3 - Article
C2 - 21414315
AN - SCOPUS:79954445413
VL - 585
SP - 1147
EP - 1152
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 8
ER -